Techniques for applying, configuring, and coordinating nerve fiber stimulation

ABSTRACT

Apparatus is provided including an implantable sensor, adapted to sense an electrical parameter of a heart of a subject, and a first control unit, adapted to apply pulses to the heart responsively to the sensed parameter, the pulses selected from the list consisting of: pacing pulses and anti-arrhythmic energy. The apparatus further includes an electrode device, adapted to be coupled to a site of the subject selected from the list consisting of: a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject; and a second control unit, adapted to drive the electrode device to apply to the site a current that increases parasympathetic tone of the subject and affects a heart rate of the subject. The first and second control units are not under common control. At least one of the control units is adapted to coordinate an aspect of its operation with an aspect of operation of the other control unit. Other embodiments are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation-in-part of a US applicationfiled Feb. 18, 2005, entitled, “Techniques for applying, calibrating,and controlling nerve fiber stimulation,” which is acontinuation-in-part of U.S. patent application Ser. No. 10/719,659 toBen David et al., filed Nov. 20, 2003, entitled, “Selective nerve fiberstimulation for treating heart conditions,” which is acontinuation-in-part of PCT Patent Application PCT/IL03/00431, filed May23, 2003, entitled, “Selective nerve fiber stimulation for treatingheart conditions,” which: (a) is a continuation-in-part of U.S. patentapplication Ser. No. 10/205,475, filed Jul. 24, 2002, entitled,“Selective nerve fiber stimulation for treating heart conditions,” whichis a continuation-in-part of PCT Patent Application PCT/IL02/00068,filed Jan. 23, 2002, entitled, “Treatment of disorders by unidirectionalnerve stimulation,” which is a continuation-in-part of U.S. patentapplication Ser. No. 09/944,913, filed Aug. 31, 2001, entitled,“Treatment of disorders by unidirectional nerve stimulation”; and (b)claims the benefit of U.S. Provisional Patent Application 60/383,157 toAyal et al., filed May 23, 2002, entitled, “Inverse recruitment forautonomic nerve systems.”

All of the above-mentioned applications are assigned to the assignee ofthe present application and are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to treating subjects byapplication of electrical signals to a selected nerve or nerve bundle,and specifically to methods and apparatus for stimulating the vagusnerve for treating heart conditions.

BACKGROUND OF THE INVENTION

The use of nerve stimulation for treating and controlling a variety ofmedical, psychiatric, and neurological disorders has seen significantgrowth over the last several decades. In particular, stimulation of thevagus nerve (the tenth cranial nerve, and part of the parasympatheticnervous system) has been the subject of considerable research. The vagusnerve is composed of somatic and visceral afferents (inward conductingnerve fibers, which convey impulses toward the brain) and efferents(outward conducting nerve fibers, which convey impulses to an effectorto regulate activity such as muscle contraction or glandular secretion).

The rate of the heart is restrained in part by parasympathetic activityfrom the right and left vagus nerves. Low vagal nerve activity isconsidered to be related to various arrhythmias, including tachycardia,ventricular accelerated rhythm, and rapid atrial fibrillation. Byartificially stimulating the vagus nerves, it is possible to slow theheart, allowing the heart to more completely relax and the ventricles toexperience increased filling. With larger diastolic volumes, the heartmay beat more efficiently because it may expend less energy to overcomethe myocardial viscosity and elastic forces of the heart with each beat.

Stimulation of the vagus nerve has been proposed as a method fortreating various heart conditions, including heart failure and atrialfibrillation. Heart failure is a cardiac condition characterized by adeficiency in the ability of the heart to pump blood throughout the bodyand/or to prevent blood from backing up in the lungs. Customarytreatment of heart failure includes medication and lifestyle changes. Itis often desirable to lower the heart rates of subjects suffering fromfaster than normal heart rates. The effectiveness of beta blockers intreating heart disease is attributed in part to theirheart-rate-lowering effect.

Bilgutay et al., in “Vagal tuning: a new concept in the treatment ofsupraventricular arrhythmias, angina pectoris, and heart failure,” J.Thoracic Cardiovas. Surg. 56 (1):71-82, July, 1968, which isincorporated herein by reference, studied the use of apermanently-implanted device with electrodes to stimulate the rightvagus nerve for treatment of supraventricular arrhythmias, anginapectoris, and heart failure. Experiments were conducted to determineamplitudes, frequencies, wave shapes and pulse lengths of thestimulating current to achieve slowing of the heart rate. The authorsadditionally studied an external device, triggered by the R-wave of theelectrocardiogram (ECG) of the subject to provide stimulation only uponan achievement of a certain heart rate. They found that when a pulsatilecurrent with a frequency of ten pulses per second and 0.2 millisecondspulse duration was applied to the vagus nerve, the heart rate could bedecreased to half the resting rate while still preserving sinus rhythm.Low amplitude vagal stimulation was employed to control inducedtachycardias and ectopic beats. The authors further studied the use ofthe implanted device in conjunction with the administration of Isuprel,a sympathomimetic drug. They found that Isuprel retained its inotropiceffect of increasing contractility, while its chronotropic effect wascontrolled by the vagal stimulation: “An increased end diastolic volumebrought about by slowing of the heart rate by vagal tuning, coupled withincreased contractility of the heart induced by the inotropic effect ofIsuprel, appeared to increase the efficiency of cardiac performance” (p.79).

U.S. Pat. No. 6,473,644 to Terry, Jr. et al., which is incorporatedherein by reference, describes a method for treating patients sufferingfrom heart failure to increase cardiac output, by stimulating ormodulating the vagus nerve with a sequence of substantiallyequally-spaced pulses by an implanted neurostimulator. The frequency ofthe stimulating pulses is adjusted until the patient's heart ratereaches a target rate within a relatively stable target rate range belowthe low end of the patient's customary resting heart rate.

US Patent Application Publication 2003/0040774 to Terry et al., which isincorporated herein by reference, describes a device for treatingpatients suffering from congestive heart failure. The device includes animplantable neurostimulator for stimulating the patient's vagus nerve ator above the cardiac branch with an electrical pulse waveform at astimulating rate sufficient to maintain the patient's heart beat at arate well below the patient's normal resting heart rate, therebyallowing rest and recovery of the heart muscle, to increase in coronaryblood flow, and/or growth of coronary capillaries. A metabolic needsensor detects the patient's current physical state and concomitantlysupplies a control signal to the neurostimulator to vary the stimulatingrate. If the detection indicates a state of rest, the neurostimulatorrate reduces the patient's heart rate below the patient's normal restingrate. If the detection indicates physical exertion, the neurostimulatorrate increases the patient's heart rate above the normal resting rate.

U.S. Patent Publication 2003/0045909 to Gross et al., which is assignedto the assignee of the present patent application and is incorporatedherein by reference, describes apparatus for treating a heart conditionof a subject, including an electrode device, which is adapted to becoupled to a vagus nerve of the subject. A control unit is adapted todrive the electrode device to apply to the vagus nerve a stimulatingcurrent, which is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the vagusnerve. The control unit is also adapted to drive the electrode device toapply to the vagus nerve an inhibiting current, which is capable ofinhibiting the induced action potentials traveling in the therapeuticdirection in the second set of nerve fibers, the nerve fibers in thesecond set having generally larger diameters than the nerve fibers inthe first set.

U.S. Pat. Nos. 6,272,377 and 6,400,982 to Sweeney et al., which areincorporated herein by reference, describe a cardiac rhythm managementsystem that predicts when an arrhythmia will occur and invokes a therapyto prevent or reduce the consequences of the arrhythmia. A cardiacarrhythmia trigger/marker is detected from a patient, and based on thetrigger/marker, the system estimates a probability of a cardiacarrhythmia occurring during a predetermined future time interval. Thesystem provides a list of triggers/markers, for which detection valuesare recurrently obtained at various predetermined time intervals. Basedon detection values and conditional probabilities associated with thetriggers/markers, a probability estimate of a future arrhythmia iscomputed. An arrhythmia prevention therapy is selected and activatedbased on the probability estimate of the future arrhythmia.

U.S. Pat. Nos. 5,411,531 and 5,507,784 to Hill et al., which areincorporated herein by reference, describe a device for controlling theduration of A-V conduction intervals in a patient's heart. Stimulationof the AV nodal fat pad is employed to maintain the durations of the A-Vconduction intervals within a desired interval range, which may vary asa function of sensed heart rate or other physiological parameter. AVnodal fat pad stimulation may also be triggered in response to definedheart rhythms such as a rapid rate or the occurrence of prematureventricular depolarizations, to terminate or prevent induction ofarrhythmias.

U.S. Pat. No. 6,628,987 to Hill et al., which is incorporated herein byreference, describes a system for performing a medical procedure, suchas surgery. The system comprises a sensor to sense a state of cardiactissue, such as an impending contraction and an indicator to indicatethe state of the cardiac tissue.

U.S. Pat. No. 6,449,507 to Hill et al., which is incorporated herein byreference, describes a method for performing a medical procedure, suchas surgery. A nerve is stimulated in order to adjust the beating of theheart to a first condition, such as a stopped or slowed condition. Themedical procedure is performed on the heart or another organ. Thestimulation of the nerve is stopped in order to adjust the beating ofthe heart to a second condition, such as a beating condition. The heartitself may also be stimulated to a beating condition, such as by pacing.The stimulation of the nerve may be continued in order to allow themedical procedure to be continued.

U.S. Pat. No. 6,542,774 to Hill et al., which is incorporated herein byreference, describes an electro-stimulation device including a pair ofelectrodes for connection to at least one location in the body thataffects or regulates the heartbeat. The electro-stimulation device bothelectrically arrests the heartbeat and stimulates the heartbeat.

U.S. Patent Application 2003/0216775 to Hill et al., which isincorporated herein by reference, describes a system for performing amedical procedure, such as surgery. The system comprises a compressionmember for compressing a body portion and a means for controlling thecompression.

U.S. Patent Application 2002/0035335 to Schauerte, which is incorporatedherein by reference, describes an implantable device for diagnosing anddistinguishing supraventricular and ventricular tachycardias. The deviceincludes electrodes for stimulating parasympathetic nerves of theatrioventricular and/or sinus node; electrodes for stimulating the atriaand ventricles and/or for ventricular cardioversion/defibrillation; adevice for producing electrical parasympathetic stimulation pulsespassed to the electrodes; a device for detecting the atrial and/orventricular rate, by ascertaining a time interval between atrial and/orventricular depolarization; a device for programming a frequency limitabove which a rate of the ventricles is recognized as tachycardia; acomparison device for comparing the measured heart rate duringparasympathetic stimulation to the heart rate prior to or withoutparasympathetic stimulation and/or to the frequency limit, whichdelivers an output signal when with parasympathetic stimulation theheart rate falls below the comparison value by more than a predeterminedamount; and an inhibition unit which responds to the output signal toinhibit ventricular myocardial over-stimulation therapy.

U.S. Pat. Nos. 6,240,314 and 6,493,585 to Plicchi et al., which areincorporated herein by reference, describe electrodes adapted togenerate electrical stimulation pulses at at least one first intensitylevel and at at least one second intensity level. The first and secondintensity levels are above and below a given stimulation threshold,respectively. The synchronous or asynchronous delivery of second-levelpulses is described as enabling the conduction of the atrioventricularnode to be modulated by electrotonic effect, for example, to reduceventricular frequency in the event of atrial fibrillation.

U.S. Pat. No. 6,381,499 to Taylor et al., which is incorporated hereinby reference, describes techniques for facilitating coronary surgery onthe beating heart by electrically stimulating the vagus nerve topurposely temporarily stop or substantially reduce the beating of theheart under precisely controlled conditions.

U.S. Pat. No. 6,564,096 to Mest, which is incorporated herein byreference, describes a method for regulating the heart rate of apatient, comprising inserting into a blood vessel of the patient acatheter having an electrode assembly at its distal end. The electrodeassembly comprises a generally circular main region that is generallytransverse to the axis of the catheter and on which is mounted at leastone electrode. The catheter is directed to an intravascular locationwherein the at least one electrode on the electrode assembly is adjacenta selected cardiac sympathetic or parasympathetic nerve. A stimulus isdelivered through the at least one electrode, the stimulus beingselected to stimulate the adjacent sympathetic or parasympathetic nerveto thereby cause a regulation of the patient's heart rate.

The effect of vagal stimulation on heart rate and other aspects of heartfunction, including the relationship between the timing of vagalstimulation within the cardiac cycle and the induced effect on heartrate, has been studied in animals. For example, Zhang Y et al., in“Optimal ventricular rate slowing during atrial fibrillation by feedbackAV nodal-selective vagal stimulation,” Am J Physiol Heart Circ Physiol282:H1102-H1110 (2002), describe the application of selective vagalstimulation by varying the nerve stimulation intensity, in order toachieve graded slowing of heart rate. This article is incorporatedherein by reference.

The following articles and book, which are incorporated herein byreference, may be of interest:

-   Levy M N et al., in “Parasympathetic Control of the Heart,” Nervous    Control of Vascular Function, Randall W C ed., Oxford University    Press (1984)-   Levy M N et al. ed., Vagal Control of the Heart: Experimental Basis    and Clinical Implications (The Bakken Research Center Series Volume    7), Futura Publishing Company, Inc., Armonk, N.Y. (1993)-   Randall W C ed., Neural Regulation of the Heart, Oxford University    Press (1977), particularly pages 100-106.-   Armour J A et al. eds., Neurocardiology, Oxford University Press    (1994)-   Perez M G et al., “Effect of stimulating non-myelinated vagal axon    on atrio-ventricular conduction and left ventricular function in    anaesthetized rabbits,” Auton Neurosco 86 (2001)-   Jones, J F X et al., “Heart rate responses to selective stimulation    of cardiac vagal C fibres in anaesthetized cats, rats and rabbits,”    J Physiol 489 (Pt 1):203-14 (1995)-   Wallick D W et al., “Effects of ouabain and vagal stimulation on    heart rate in the dog,” Cardiovasc. Res., 18 (2):75-9 (1984)-   Martin P J et al., “Phasic effects of repetitive vagal stimulation    on atrial contraction,” Circ. Res. 52 (6):657-63 (1983)-   Wallick D W et al., “Effects of repetitive bursts of vagal activity    on atrioventricular junctional rate in dogs,” Am J Physiol 237    (3):H275-81 (1979)-   Wallick D W et al., “Selective AV nodal vagal stimulation improves    hemodynamics during acute atrial fibrillation in dogs,” Am J Physiol    Heart Circ Physiol 281: H1490-H1497 (2001)-   Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice    Guidelines—Executive Summary,” J Am Coll Cardiol 38 (4):1231-65    (2001)-   Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice Guidelines—Full    Text,” J Am Coll Cardiol 38 (4): 1266i-12661xx (2001)-   Morady F et al., “Effects of resting vagal tone on accessory    atrioventricular connections,” Circulation 81 (1):86-90 (1990)-   Waninger M S et al., “Electrophysiological control of ventricular    rate during atrial fibrillation,” PACE 23:1239-1244 (2000)-   Wijffels M C et al., “Electrical remodeling due to atrial    fibrillation in chronically instrumented conscious goats: roles of    neurohumoral changes, ischemia, atrial stretch, and high rate of    electrical activation,” Circulation 96 (10):3710-20 (1997)-   Wijffels M C et al., “Atrial fibrillation begets atrial    fibrillation,” Circulation 92:1954-1968 (1995)-   Goldberger A L et al., “Vagally-mediated atrial fibrillation in    dogs: conversion with bretylium tosylate,” Int J Cardiol 13    (1):47-55 (1986)-   Takei M et al., “Vagal stimulation prior to atrial rapid pacing    protects the atrium from electrical remodeling in anesthetized    dogs,” Jpn Circ J 65 (12):1077-81 (2001)-   Friedrichs G S, “Experimental models of atrial    fibrillation/flutter,” J Pharmacological and Toxicological Methods    43:117-123 (2000)-   Hayashi H et al., “Different effects of class Ic and III    antiarrhythmic drugs on vagotonic atrial fibrillation in the canine    heart,” Journal of Cardiovascular Pharmacology 31:101-107 (1998)-   Morillo C A et al., “Chronic rapid atrial pacing. Structural,    functional, and electrophysiological characteristics of a new model    of sustained atrial fibrillation,” Circulation 91:1588-1595 (1995)-   Lew S J et al., “Stroke prevention in elderly patients with atrial    fibrillation,” Singapore Med J 43 (4):198-201 (2002)-   Higgins C B, “Parasympathetic control of the heart,” Pharmacol. Rev.    25:120-155 (1973)-   Hunt R, “Experiments on the relations of the inhibitory to the    accelerator nerves of the heart,” J. Exptl. Med. 2:151-179 (1897)-   Billette J et al., “Roles of the AV junction in determining the    ventricular response to atrial fibrillation,” Can J Physiol    Pharamacol 53 (4) 575-85 (1975)-   Stramba-Badiale M et al., “Sympathetic-Parasympathetic Interaction    and Accentuated Antagonism in Conscious Dogs,” American Journal of    Physiology 260 (2Pt 2):H335-340 (1991)-   Garrigue S et al., “Post-ganglionic vagal stimulation of the    atrioventricular node reduces ventricular rate during atrial    fibrillation,” PACE 21 (4), 878 (Part II) (1998)-   Kwan H et al., “Cardiovascular adverse drug reactions during    initiation of antiarrhythmic therapy for atrial fibrillation,” Can J    Hosp Pharm 54:10-14 (2001)-   Jidéus L, “Atrial fibrillation after coronary artery bypass surgery:    A study of causes and risk factors,” Acta Universitatis Upsaliensis,    Uppsala, Sweden (2001)-   Borovikova L V et al., “Vagus nerve stimulation attenuates the    systemic inflammatory response to endotoxin,” Nature 405    (6785):458-62 (2000)-   Wang H et al., “Nicotinic acetylcholine receptor alpha-7 subunit is    an essential regulator of inflammation,” Nature 421:384-388 (2003)-   Vanoli E et al., “Vagal stimulation and prevention of sudden death    in conscious dogs with a healed myocardial infarction,” Circ Res 68    (5):1471-81 (1991)-   De Ferrari G M, “Vagal reflexes and survival during acute myocardial    ischemia in conscious dogs with healed myocardial infarction,” Am J    Physiol 261 (1 Pt 2):H63-9 (1991)-   Li D et al., “Promotion of Atrial Fibrillation by Heart Failure in    Dogs: Atrial Remodeling of a Different Sort,” Circulation 100    (1):87-95 (1999)-   Feliciano L et al., “Vagal nerve stimulation during muscarinic and    beta-adrenergic blockade causes significant coronary artery    dilation,” Cardiovasc Res 40 (1):45-55 (1998)-   Carlson M D et al., “Selective stimulation of parasympathetic nerve    fibers to the human sinoatrial node,” Circulation 85:1311-1317    (1992)-   Pagé P L et al., “Regional distribution of atrial electrical changes    induced by stimulation of extracardiac and intracardiac neural    elements,” J Thorac Cardiovasc Surg 109 (2):377-88 (1995)-   Masato Tsuboi et al., “Inotropic, chronotropic, and dromotropic    effects mediated via parasympathetic ganglia in the dog heart,” Am J    Physiol Heart Circ Physiol 279: H1201-H1207 (2000)-   Furukawa Y et al., “Differential blocking effects of atropine and    gallamine on negative chronotropic and dromotropic responses to    vagus stimulation in anesthetized dogs,” J Pharmacol Exp Ther 251    (3):797-802 (1989)-   Bluemel K M, “Parasympathetic postganglionic pathways to the    sinoatrial node,” J Physiol 259 (5 Pt 2):H1504-10 (1990)-   Mazgalev T N, “AV Nodal Physiology,” Heart Rhythm Society    (www.hrsonline.org) (no date)-   Bibevski S et al., “Ganglionic Mechanisms Contribute to Diminished    Vagal Control in Heart Failure,” Circulation 99:2958-2963 (1999)-   Hirose M et al., “Pituitary Adenylate Cyclase-Activating    Polypeptide-27 Causes a Biphasic Chronotropic Effect and Atrial    Fibrillation in Autonomically Decentralized, Anesthetized Dogs,” J    Pharmacol Exp Ther 283 (2):478-87 (1997)-   Chen S A et al., “Intracardiac stimulation of human parasympathetic    nerve fibers induces negative dromotropic effects: implication with    the lesions of radiofrequency catheter ablation,” J Cardiovasc    Electrophysiol 9 (3):245-52 (1998)-   Cooper et al., “Neural effects on sinus rate and atrial ventricular    conduction produced by electrical stimulation from a transvenous    electrode catheter in the canine right pulmonary artery” Circ Res    Vol. 46 (1):48-57 (1980)

Heart rate variability is considered an important determinant of cardiacfunction. Heart rate normally fluctuates within a normal range in orderto accommodate constantly changing physiological needs. For example,heart rate increases during waking hours, exertion, and inspiration, anddecreases during sleeping, relaxation, and expiration. Tworepresentations of heart rate variability are commonly used: (a) thestandard deviation of beat-to-beat R-R interval differences within acertain time window (i.e., variability in the time domain), and (b) themagnitude of variability as a function of frequency (i.e., variabilityin the frequency domain).

Short-term (beat-to-beat) variability in heart rate represents fast,high-frequency (HF) changes in heart rate. For example, the changes inheart rate associated with breathing are characterized by a frequency ofbetween about 0.15 and about 0.4 Hz (corresponding to a time constantbetween about 2.5 and 7 seconds). Low-frequency (LF) changes in heartrate (for example, blood pressure variations) are characterized by afrequency of between about 0.04 and about 0.15 Hz (corresponding to atime constant between about 7 and 25 seconds). Very-low-frequency (VLF)changes in heart rate are characterized by a frequency of between about0.003 and about 0.04 Hz (0.5 to 5 minutes). Ultra-low-frequency (ULF)changes in heart rate are characterized by a frequency of between about0.0001 and about 0.003 Hz (5 minutes to 2.75 hours). A commonly usedindicator of heart rate variability is the ratio of HF power to LFpower.

High heart rate variability (especially in the high frequency range, asdescribed hereinabove) is generally correlated with a good prognosis inconditions such as ischemic heart disease and heart failure. In otherconditions, such as atrial fibrillation, increased heart ratevariability in an even higher frequency range can cause a reduction incardiac efficiency by producing beats that arrive too quickly (when theventricle is not optimally filled) and beats that arrive too late (whenthe ventricle is fully filled and the pressure is too high).

Kamath et al., in “Effect of vagal nerve electrostimulation on the powerspectrum of heart rate variability in man,” Pacing Clin Electrophysiol15:235-43 (1992), describe an increase in the ratio of low frequency tohigh frequency components of the peak power spectrum of heart ratevariability during a period without vagal stimulation, compared toperiods with vagal stimulation. Iwao et al., in “Effect of constant andintermittent vagal stimulation on the heart rate and heart ratevariability in rabbits,” Jpn J Physiol 50:33-9 (2000), describe nochange in heart rate variability caused by respiration in all modes ofstimulation with respect to baseline data. Each of these articles isincorporated herein by reference.

The following articles, which are incorporated herein by reference, maybe of interest:

Kleiger R E et al., “Decreased heart rate variability and itsassociation with increased mortality after myocardial infarction,” Am JCardiol 59: 256-262 (1987)

Akselrod S et al., “Power spectrum analysis of heart rate fluctuation: aquantitative probe of beat-to-beat cardiovascular control,” Science 213:220-222 (1981)

A number of patents describe techniques for treating arrhythmias and/orischemia by, at least in part, stimulating the vagus nerve. Arrhythmiasin which the heart rate is too fast include fibrillation, flutter andtachycardia. Arrhythmia in which the heart rate is too slow is known asbradyarrhythmia. U.S. Pat. No. 5,700,282 to Zabara, which isincorporated herein by reference, describes techniques for stabilizingthe heart rhythm of a patient by detecting arrhythmias and thenelectronically stimulating the vagus and cardiac sympathetic nerves ofthe patient. The stimulation of vagus efferents directly causes theheart rate to slow down, while the stimulation of cardiac sympatheticnerve efferents causes the heart rate to quicken.

U.S. Pat. No. 5,330,507 to Schwartz, which is incorporated herein byreference, describes a cardiac pacemaker for preventing or interruptingtachyarrhythmias and for applying pacing therapies to maintain the heartrhythm of a patient within acceptable limits. The device automaticallystimulates the right or left vagus nerves as well as the cardiac tissuein a concerted fashion dependent upon need. Continuous and/or phasicelectrical pulses are applied. Phasic pulses are applied in a specificrelationship with the R-wave of the ECG of the patient.

European Patent Application EP 0 688 577 to Holmstrom et al., which isincorporated herein by reference, describes a device to treat atrialtachyarrhythmia by detecting arrhythmia and stimulating aparasympathetic nerve that innervates the heart, such as the vagusnerve.

U.S. Pat. Nos. 5,690,681 and 5,916,239 to Geddes et al., which areincorporated herein by reference, describe closed-loop,variable-frequency, vagal-stimulation apparatus for control ofventricular rate during atrial fibrillation. The apparatus stimulatesthe left vagus nerve, and automatically and continuously adjusts thevagal stimulation frequency as a function of the difference betweenactual and desired ventricular excitation rates. In an alternativeembodiment, the apparatus automatically adjusts the vagal stimulationfrequency as a function of the difference between ventricular excitationrate and arterial pulse rate in order to eliminate or minimize pulsedeficit.

U.S. Patent Publication 2003/0229380 to Adams et al., which isincorporated herein by reference, describes techniques for electricallystimulating the right vagus nerve in order to reduce the heart rate of apatient suffering from conditions such as chronic heart failure,ischemia, or acute myocardial infarction. The amount of energy of thestimulation may be determined in accordance with a difference betweenthe patient's actual heart rate and a maximum target heart rate for thepatient. Delivery of energy is preferably synchronized with thedetection of a P-wave. Automatic adjustment of the target heart rate maybe based on current day and/or time of day information, and patientphysical activity. The voltage, pulse width, or number of pulses in thestimulation may be controlled.

U.S. Pat. No. 5,203,326 to Collins, which is incorporated herein byreference, describes an antiarrhythmia pacemaker which detects a cardiacabnormality and responds with electrical stimulation of the heartcombined with vagus nerve stimulation. The pacemaker controls electricalstimulation of the heart in terms of timing, frequency, amplitude,duration and other operational parameters, to provide such pacingtherapies as antitachycardia pacing, cardioversion, and defibrillation.The vagal stimulation frequency is progressively increased in one-minuteintervals, and, for the pulse delivery rate selected, the heart rate isdescribed as being slowed to a desired, stable level by increasing thepulse current.

U.S. Pat. No. 6,511,500 to Rahme, which is incorporated herein byreference, describes various aspects of the effects of autonomic nervoussystem tone on atrial arrhythmias, and its interaction with class mantiarrhythmic drug effects. The significance of sympathetic andparasympathetic activation are described as being evaluated bydetermining the effects of autonomic nervous system using vagal andstellar ganglions stimulation, and by using autonomic nervous systemneurotransmitters infusion (norepinephrine, acetylcholine).

U.S. Pat. No. 5,199,428 to Obel et al., which is incorporated herein byreference, describes a cardiac pacemaker for detecting and treatingmyocardial ischemia. The device automatically stimulates the vagalnervous system as well as the cardiac tissue in a concerted fashion inorder to decrease cardiac workload and thereby protect the myocardium.

U.S. Pat. Nos. 5,334,221 to Bardy and U.S. Pat. No. 5,356,425 to Bardyet al., which are incorporated herein by reference, describe astimulator for applying stimulus pulses to the AV nodal fat pad inresponse to the heart rate exceeding a predetermined rate, in order toreduce the ventricular rate. The device also includes a cardiacpacemaker which serves to pace the ventricle in the event that theventricular rate is lowered below a pacing rate, and provides forfeedback control of the stimulus parameters applied to the AV nodal fatpad, as a function of the determined effect of the stimulus pulses onthe heart rate.

U.S. Pat. No. 5,522,854 to Ideker et al., which is incorporated hereinby reference, describes techniques for preventing arrhythmia bydetecting a high risk of arrhythmia and then stimulating afferent nervesto prevent the arrhythmia.

U.S. Pat. No. 6,434,424 to Igel et al., which is incorporated herein byreference, describes a pacing system with a mode switching feature andventricular rate regularization function adapted to stabilize orregularize ventricular heart rate during chronic or paroxysmal atrialtachyarrhythmia.

U.S. Patent Application Publication 2002/0120304 to Mest, which isincorporated herein by reference, describes a method for regulating theheart rate of a patient by inserting into a blood vessel of the patienta catheter having an electrode at its distal end, and directing thecatheter to an intravascular location so that the electrode is adjacentto a selected cardiac sympathetic or parasympathetic nerve.

U.S. Pat. Nos. 6,006,134 and 6,266,564 to Hill et al., which areincorporated herein by reference, describe an electro-stimulation deviceincluding a pair of electrodes for connection to at least one locationin the body that affects or regulates the heartbeat.

PCT Publication WO 02/085448 to Foreman et al., which is incorporatedherein by reference, describes a method for protecting cardiac functionand reducing the impact of ischemia on the heart, by electricallystimulating a neural structure capable of carrying the predeterminedelectrical signal from the neural structure to the “intrinsic cardiacnervous system,” which is defined and described therein.

U.S. Pat. No. 5,243,980 to Mehra, which is incorporated herein byreference, describes techniques for discrimination between ventricularand supraventricular tachycardia. In response to the detection of theoccurrence of a tachycardia, stimulus pulses are delivered to one orboth of the SA and AV nodal fat pads. The response of the heart rhythmto these stimulus pulses is monitored. Depending upon the change or lackof change in the heart rhythm, a diagnosis is made as to the origin ofthe tachycardia.

U.S. Pat. No. 5,658,318 to Stroetmann et al., which is incorporatedherein by reference, describes a device for detecting a state ofimminent cardiac arrhythmia in response to activity in nerve signalsconveying information from the autonomic nerve system to the heart. Thedevice comprises a sensor adapted to be placed in an extracardiacposition and to detect activity in at least one of the sympathetic andvagus nerves.

U.S. Pat. No. 6,292,695 to Webster, Jr. et al., which is incorporatedherein by reference, describes a method for controlling cardiacfibrillation, tachycardia, or cardiac arrhythmia by the use of acatheter comprising a stimulating electrode, which is placed at anintravascular location. The electrode is connected to a stimulatingmeans, and stimulation is applied across the wall of the vessel,transvascularly, to a sympathetic or parasympathetic nerve thatinnervates the heart at a strength sufficient to depolarize the nerveand effect the control of the heart.

U.S. Pat. No. 6,134,470 to Hartlaub, which is incorporated herein byreference, describes an implantable anti-arrhythmia system whichincludes a spinal cord stimulator coupled to an implantable heart rhythmmonitor. The monitor is adapted to detect the occurrence oftachyarrhythmias or of precursors thereto and, in response, trigger theoperation of the spinal cord stimulator in order to prevent occurrencesof tachyarrhythmias and/or as a stand-alone therapy for termination oftachyarrhythmias and/or to reduce the level of aggressiveness requiredof an additional therapy such as antitachycardia pacing, cardioversionor defibrillation.

A number of patents and articles describe other methods and devices forstimulating nerves to achieve a desired effect. Often these techniquesinclude a design for an electrode or electrode cuff.

U.S. Patent Publication 2003/0050677 to Gross et al., which is assignedto the assignee of the present patent application and is incorporatedherein by reference, describes apparatus for applying current to anerve. A cathode is adapted to be placed in a vicinity of a cathodiclongitudinal site of the nerve and to apply a cathodic current to thenerve. A primary inhibiting anode is adapted to be placed in a vicinityof a primary anodal longitudinal site of the nerve and to apply aprimary anodal current to the nerve. A secondary inhibiting anode isadapted to be placed in a vicinity of a secondary anodal longitudinalsite of the nerve and to apply a secondary anodal current to the nerve,the secondary anodal longitudinal site being closer to the primaryanodal longitudinal site than to the cathodic longitudinal site.

U.S. Pat. Nos. 4,608,985 to Crish et al. and U.S. Pat. No. 4,649,936 toUngar et al., which are incorporated herein by reference, describeelectrode cuffs for selectively blocking orthodromic action potentialspassing along a nerve trunk, in a manner intended to avoid causing nervedamage.

PCT Patent Publication WO 01/10375 to Felsen et al., which isincorporated herein by reference, describes apparatus for modifying theelectrical behavior of nervous tissue. Electrical energy is applied withan electrode to a nerve in order to selectively inhibit propagation ofan action potential.

U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated hereinby reference, describes techniques for selectively blocking differentsize fibers of a nerve by applying direct electric current between ananode and a cathode that is larger than the anode. The current appliedto the electrodes blocks nerve transmission, but, as described, does notactivate the nerve fibers in either direction.

U.S. Pat. No. 6,600,956 to Maschino et al., which is incorporated hereinby reference, describes an electrode assembly to be installed on apatient's nerve. The electrode assembly has a thin, flexible,electrically insulating circumneural carrier with a splitcircumferential configuration longitudinally attached to a lead at thedistal end thereof. The carrier possesses circumferential resiliency andhas at least one flexible, elastic electrode secured to the undersidethereof and electrically connected to an electrical conductor in saidlead. A fastener serves to close the split configuration of the carrierto prevent separation from the nerve after installation of the electrodeassembly onto the nerve. Tear away webbing secured to adjacentserpentine segments of the lead near the carrier enables the lead tolengthen with patient movements.

The following articles, which are incorporated herein by reference, maybe of interest:

-   Ungar I J et al., “Generation of unidirectionally propagating action    potentials using a monopolar electrode cuff,” Annals of Biomedical    Engineering, 14:437-450 (1986)-   Sweeney J D et al., “An asymmetric two electrode cuff for generation    of unidirectionally propagated action potentials,” IEEE Transactions    on Biomedical Engineering, vol. BME-33 (6) (1986)-   Sweeney J D et al., “A nerve cuff technique for selective excitation    of peripheral nerve trunk regions,” IEEE Transactions on Biomedical    Engineering, 37 (7) (1990)-   Naples G G et al., “A spiral nerve cuff electrode for peripheral    nerve stimulation,” by IEEE Transactions on Biomedical Engineering,    35 (11) (1988)-   van den Honert C et al., “Generation of unidirectionally propagated    action potentials in a peripheral nerve by brief stimuli,” Science,    206:1311-1312 (1979)-   van den Honert C et al., “A technique for collision block of    peripheral nerve: Single stimulus analysis,” MP-11, IEEE Trans.    Biomed. Eng. 28:373-378 (1981)-   van den Honert C et al., “A technique for collision block of    peripheral nerve: Frequency dependence,” MP-12, IEEE Trans. Biomed.    Eng. 28:379-382 (1981)-   Rijkhoff N J et al., “Acute animal studies on the use of anodal    block to reduce urethral resistance in sacral root stimulation,”    IEEE Transactions on Rehabilitation Engineering, 2 (2):92 (1994)-   Mushahwar V K et al., “Muscle recruitment through electrical    stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil    Eng, 8 (1):22-9 (2000)-   Deurloo K E et al., “Transverse tripolar stimulation of peripheral    nerve: a modelling study of spatial selectivity,” Med Biol Eng    Comput, 36 (1):66-74 (1998)-   Tarver W B et al., “Clinical experience with a helical bipolar    stimulating lead,” Pace, Vol. 15, October, Part II (1992)-   Manfredi M, “Differential block of conduction of larger fibers in    peripheral nerve by direct current,” Arch. Ital. Biol., 108:52-71    (1970)

In physiological muscle contraction, nerve fibers are recruited in theorder of increasing size, from smaller-diameter fibers to progressivelylarger-diameter fibers. In contrast, artificial electrical stimulationof nerves using standard techniques recruits fibers in a larger- tosmaller-diameter order, because larger-diameter fibers have a lowerexcitation threshold. This unnatural recruitment order causes musclefatigue and poor force gradation. Techniques have been explored to mimicthe natural order of recruitment when performing artificial stimulationof nerves to stimulate muscles.

Fitzpatrick et al., in “A nerve cuff design for the selective activationand blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. inMedicine and Biology Soc, 13 (2), 906 (1991), which is incorporatedherein by reference, describe a tripolar electrode used for musclecontrol. The electrode includes a central cathode flanked on itsopposite sides by two anodes. The central cathode generates actionpotentials in the motor nerve fiber by cathodic stimulation. One of theanodes produces a complete anodal block in one direction so that theaction potential produced by the cathode is unidirectional. The otheranode produces a selective anodal block to permit passage of the actionpotential in the opposite direction through selected motor nerve fibersto produce the desired muscle stimulation or suppression.

The following articles, which are incorporated herein by reference, maybe of interest:

-   Rijkhoff N J et al., “Orderly recruitment of motoneurons in an acute    rabbit model,” Ann. Conf. of the IEEE Eng., Medicine and Biology    Soc., 20 (5):2564 (1998)-   Rijkhoff N J et al., “Selective stimulation of small diameter nerve    fibers in a mixed bundle,” Proceedings of the Annual Project Meeting    Sensations/Neuros and Mid-Term Review Meeting on the TMR-Network    Neuros, Apr. 21-23, 1999, pp. 20-21 (1999)-   Baratta R et al., “Orderly stimulation of skeletal muscle motor    units with tripolar nerve cuff electrode,” IEEE Transactions on    Biomedical Engineering, 36 (8):836-43 (1989)-   Levy M N, Blattberg B., “Effect of vagal stimulation on the overflow    of norepinephrine into the coronary sinus during sympathetic nerve    stimulation in the dog,” Circ Res 1976 February; 38 (2):81-4-   Lavallee et al. “Muscarinic inhibition of endogenous myocardial    catecholamine liberation in the dog,” Can J Physiol Pharmacol 1978    August; 56 (4):642-9-   Mann D L, Kent R L, Parsons B, Cooper G, “Adrenergic effects on the    biology of the adult mammalian cardiocyte,” Circulation 1992    February; 85 (2):790-804-   Mann D L, “Basic mechanisms of disease progression in the failing    heart: role of excessive adrenergic drive,” Prog Cardiovasc Dis 1998    July-August; 41 (1suppl 1):1-8-   Barzilai A, Daily D, Zilkha-Falb R, Ziv I, Offen D, Melamed E, Sirv    A, “The molecular mechanisms of dopamine toxicity,” Adv Neurol 2003;    91:73-82

The following articles, which are incorporated herein by reference,describe techniques using point electrodes to selectively exciteperipheral nerve fibers:

-   Grill W M et al., “Inversion of the current-distance relationship by    transient depolarization,” IEEE Trans Biomed Eng, 44 (1):1-9 (1997)-   Goodall E V et al., “Position-selective activation of peripheral    nerve fibers with a cuff electrode,” IEEE Trans Biomed Eng, 43    (8):851-6 (1996)-   Veraart C et al., “Selective control of muscle activation with a    multipolar nerve cuff electrode,” IEEE Trans Biomed Eng, 40    (7):640-53 (1993)

U.S. Pat. No. 6,620,186 to Saphon et al., which is incorporated hereinby reference, describes apparatus for testing the impedance of a medicallead connecting an implantable stimulation device to a nerve or amuscle.

U.S. Pat. No. 6,393,323 to Sawan et al., which is incorporated herein byreference, describes an electronic stimulator implant for modulating andsynchronizing bladder and sphincter function. The implant is connectedto an end of an electrode, and the second end thereof is connected to asacral nerve. In order to confirm that the implant is operatingproperly, the implant measures an electrode-tissue contact impedancevalue.

U.S. Pat. No. 5,891,179 to Er et al., which is incorporated herein byreference, describes techniques for monitoring and displaying leadimpedance in real-time for an implantable medical device having animplantable electrical lead. In one example, the implantable medicaldevice is a pacemaker and the impedance monitoring system is within anexternal programmer device separate from the pacemaker. The '179 patentdescribes other examples of implantable medical devices, includingdevices for stimulating or sensing nerves.

U.S. Pat. No. 6,366,813 to DiLorenzo, which is incorporated herein byreference, describes a neurological control system for modulatingactivity of a component of the nervous system, or any structureinterfaced thereto. The system generates neural modulation signalsdelivered to the nervous system component through one or moreintracranial (IC) stimulating electrodes in accordance with treatmentparameters. Such treatment parameters may be derived from a neuralresponse to previously delivered neural modulation signals sensed by oneor more sensors, each configured to sense a particular characteristicindicative of a neurological or psychiatric condition. Neural modulationsignals include any control signal which enhances or inhibits cellactivity. The neurological control system considers neural response, inthe form of the sensory feedback, as an indication of neurologicaldisease state and/or responsiveness to therapy, in the determination oftreatment parameters.

U.S. Patent Application Publication 2004/0172075 to Shafer et al., whichis incorporated herein by reference, describes techniques includingstimulating a patient's heart while stimulating a nerve of the patientin order to modulate the patient's inflammatory process. Moreparticularly, the techniques include pacing the ventricles of thepatient's heart while stimulating the vagal nerve of the patient.

U.S. Pat. No. 6,341,236 to Osorio et al., which is incorporated hereinby reference, describes techniques for electrically stimulating thevagus nerve to treat epilepsy with minimized or no effect on the heart.Treatment is carried out by an implantable signal generator, one or moreimplantable electrodes for electrically stimulating a predeterminedstimulation site of the vagus nerve, and a sensor for sensingcharacteristics of the heart such as a heart rate. The heart rateinformation from the sensor can be used to determine whether the vagusnerve stimulation is adversely affecting the heart. Once thresholdparameters are met, the vagus nerve stimulation may be stopped oradjusted. In an alternative embodiment, a modified pacemaker is used tomaintain the heart in desired conditions during the vagus nervestimulation. In yet another embodiment, a modified pacemaker havingcircuitry that determines whether a vagus nerve is being stimulated isused. In the event that the vagus nerve is being stimulated, themodified pacemaker may control the heart to maintain it within desiredconditions during the vagus nerve stimulation.

SUMMARY OF THE INVENTION

In embodiments of the present invention, a vagal stimulation system fortreating a heart condition comprises a multipolar electrode device thatis applied to a portion of a vagus nerve that innervates the heart of asubject. The vagal stimulation system further comprises an implanted orexternal control unit. Typically, the system is configured to treatheart failure and/or heart arrhythmia, such as atrial fibrillation ortachycardia.

In some embodiments of the present invention, the vagal stimulationsystem is configured to apply vagal stimulation in a series of bursts,each burst including at least one pulse. The application of each of thebursts in each cardiac cycle typically commences after a variable delayafter a detected R-wave, P-wave, or other feature of an ECG. The delayis typically calculated in real time using a function, the inputs ofwhich include one or more pre-programmed but updateable constants andone or more sensed parameters, such as the R-R interval between cardiaccycles and/or the P-R interval. Alternatively or additionally, a lookuptable of delays is used to determine in real time the appropriate delayfor the application of each of the bursts, based on the one or moresensed parameters.

In some embodiments of the present invention, the control unit isconfigured to drive the electrode device to stimulate the vagus nerve soas to reduce the heart rate of the subject towards a target heart rate.Parameters of stimulation are varied in real time in order to vary theheart-rate-lowering effects of the stimulation. In embodiments of thepresent invention in which the stimulation is applied in a series ofbursts that are synchronized with the cardiac cycle of the subject, suchas described hereinabove, parameters of such bursts typically include,but are not limited to: (a) timing of the stimulation within the cardiaccycle, (b) pulse duration (width), (c) pulse repetition interval withineach burst, (d) number of pulses per burst, also referred to herein as“pulses per trigger” (PPT), (e) amplitude, (f) duty cycle, (g) choice ofvagus nerve, and (h) “on”/“off” ratio and timing (i.e., duringintermittent operation). For some applications, the pulse repetitioninterval is maintained generally constant, while the PPT is varied toregulate the amount of stimulation applied to the vagus nerve.

In some embodiments of the present invention, in which the parameters ofthe applied bursts include an “on”/“off” ratio, as described herein, thecontrol unit is configured to apply the bursts during short “on” periodsand, optionally, to withhold the bursts during short “off” periods. Eachof the short “on” periods typically has a duration of less than about 10seconds, e.g., less than about 5 seconds. When short “off” periods areused, each of the “off” periods typically has a duration of betweenseveral seconds and several minutes. The use of such short “on” and/or“off” periods generally allows stimulation of any given strength to beapplied as effectively as when using longer “on”/“off” periods, but withfewer potential side effects. For some applications, a desired number ofpulses per time period or per heart beat is delivered more effectivelyand/or with a reduced risk of side effects, by using short “on” periods.

In some embodiments of the present invention, the control unit isconfigured to apply vagal stimulation in alternating short “high”stimulation and short “low” stimulation periods. For some applications,the “high” stimulation periods have a greater PPT than the “low”stimulation periods. Alternatively or additionally, the “high”stimulation periods have a greater amplitude than the “low” stimulationperiods. Further alternatively or additionally, the control unit adjustsone or more of the other parameters described herein in order to applythe “high” stimulation periods with a greater strength than the “low”stimulation periods. Typically, each of the “high” stimulation periodshas a duration of less than about 30 seconds (e.g., less than about 5seconds), and each of the “low” stimulation periods has a duration lessthan about 30 seconds (e.g., less than about 5 seconds).

In some embodiments of the present invention, the control unit isconfigured to apply vagal stimulation using feedback, wherein aparameter of the feedback is a target heart rate that is a function ofan average heart rate of the subject. The average heart rate istypically calculated over a period of between about 12 hours and about 2weeks. For some applications, the target heart rate is set equal orapproximately equal to the average heart rate of the subject.Alternatively, the target heart rate is set at a rate greater than theaverage heart rate of the subject, such as a percentage greater than theaverage heart rate, e.g., about 15% greater. For some applications, thecontrol unit determines the target heart rate in real time, periodicallyor substantially continuously, by sensing the heart rate of the subjectand calculating the average heart rate of the subject. For someapplications, the average heart rate is calculated over a most recenttime period, e.g., the heart rate over the last half hour.Alternatively, the average heart rate is based on a sensed average heartrate of the subject at rest, and is updated periodically, e.g., severaltimes per day.

In some embodiments of the present application, the control unit isconfigured to apply vagal stimulation when the heart rate of the subjectis below a threshold value, in order to increase the heart rate. Thethreshold value is typically determined for each subject, e.g., based onthe subject's hemodynamic needs and/or individual response to vagalstimulation. For some applications, the control unit is configured toapply fast intermittent stimulation, as defined hereinabove. In someembodiments, the control unit is configured to apply vagal stimulation(a) when the heart rate of the subject is above a first threshold value,in order to reduce the heart rate, and (b) when the heart rate is belowa second threshold value, which is lower than the first threshold value,in order to increase the heart rate. The inventors have found that vagalstimulation using the same signal parameters lowers heart rate when theheart rate is above certain threshold values, and raises heart rate whenthe heart rate is below certain threshold values. The inventors theorizethat stimulation at lower heart rates has a greater effect onsympathetic axons of the vagus nerve, while stimulation at higher heartrates has a greater effect on parasympathetic axons. It is to beemphasized that the practice of these embodiments is in no way dependentupon the correctness of this theory.

In some embodiments of the present invention, the control unit isconfigured to apply vagal stimulation having a strength that isinversely related, e.g., inversely proportional, to a heart rate of thesubject, i.e., as the heart rate increases, the strength of thestimulation is decreased. For some applications, the control unitwithholds applying the vagal stimulation when the heart rate exceeds athreshold value. Such a configuration generally results in thebeneficial effects of vagal stimulation that are not necessarilydependent on the heart-rate reduction effects of such stimulation. Sucha configuration generally also results in an improved quality of lifefor the subject, because the heart rate is allowed to meet the subject'sphysiological demands.

In some embodiments of the present invention, the control unit comprisesor is coupled to an implanted device for monitoring and correcting theheart rate, such as an implantable cardioverter defibrillator (ICD) or apacemaker (e.g., a bi-ventricular or standard pacemaker). For someapplications, the control unit is configured to apply vagal stimulationwith stimulation and/or feedback parameters that reduce the likelihoodof the vagal stimulation causing the ICD or pacemaker to falsely detectarrhythmia. Alternatively or additionally, the control unit isconfigured to apply vagal stimulation with stimulation and/or feedbackparameters that reduce the likelihood of the occurrence of a“tug-of-war” between the vagal stimulation system and the ICD orpacemaker.

In some embodiments of the present invention, the control unitimplements one or more counters, either in hardware or in softwarerunning the control unit. Such counters include, but are not limited to,a counter that counts the number of stimulations (i.e., cardiac cyclesin which stimulation is applied), a counter that counts the total numberof pulses applied to the vagus nerve during a certain period of time,and a counter that counts the number of detected heart beats during acertain period of time.

For some applications, such as when the control unit operates usingfeedback, an average PPT during stimulations is calculated by dividingthe total number of pulses applied in a given period by the number ofstimulations, i.e., bursts, applied in the period. The average PPTduring stimulations is one indication of the strength of stimulation thecontrol unit needed to apply, based on feedback, in order to maintainthe heart rate at the desired target rate.

For some applications, the control unit operates using feedback, and isconfigured to control a number of pulses applied during each burst ofstimulation, responsive to the feedback. Such feedback sometimes resultsin variations in the average number of pulses per burst. The controlunit is configured to monitor the average number of pulses per burst ina given time period. If the average number of pulses per burst exceeds amaximum threshold value over the given period of time, the control unitmodifies the parameters of stimulation so as to reduce the averagenumber of pulses per burst. For example, the maximum threshold value maybe about 3 pulses per burst. Typically, the parameters adjusted by thecontrol unit include: (a) one or more of the feedback parameters, suchas target heart rate and/or a reaction speed parameter governing thefeedback, and/or (b) one or more stimulation parameters, such asstimulation amplitude, pulse duration, and/or maximum number of pulseswithin a burst.

For some applications, the control unit operates using feedback, whichresults in a variable number of bursts per heart beat and/or per unittime. (For example, a burst may be applied every 1-60 heart beats, orevery 0.3-60 seconds, as dictated by a feedback algorithm.) Suchfeedback sometimes results in high- and/or low-frequency variations inthe duty cycle. (Duty cycle is the number of bursts applied during atime period divided by the total number of heart beats during thatperiod.) The control unit is configured to monitor the average dutycycle in a given time period. If the average exceeds a maximum thresholdvalue, the control unit adjusts one or more parameters, typicallyincluding: (a) one or more of the feedback parameters, such as targetheart rate and/or a reaction speed parameter governing the feedback,and/or (b) one or more stimulation parameters, such as amplitude, pulseduration, and/or maximum number of pulses within a burst.

For some applications, in which the control unit is configured tooperate in intermittent “on”/“off” periods, as described hereinabove,the monitored average duty cycle is used in combination with the ratioof the “on” duration to “off” duration in order to determine themagnitude of the heart-rate-lowering effect of the vagal stimulation. Aduty cycle less than the “on”/“off” ratio indicates that the stimulationis causing lowering of the heart rate, while a duty cycle equal to the“on”/“off” ratio indicates that no such lowering of the heart rate isoccurring. Typically, the control unit monitors the average duty cycleover a time period that includes at least one full “on” period and onefull “off” period, such as several “on” and “off” periods.

In some embodiments of the present invention, the control unit operatesusing feedback, and is configured to set a maximum allowable level ofstimulation. The control unit does not apply stimulation beyond thismaximum level even if the feedback algorithm calls for increasedstimulation. A physician typically sets the maximum level based onconsiderations such as possible side effects of stimulation, safety, andphysiological tolerance. Exemplary maximum levels include, but are notlimited to:

-   -   pulses per burst of between about 2 and about 20 pulses, e.g.,        about 8 pulses;    -   peak power consumption of less than 1 watt;    -   maximum continuous stimulation period, expressed in either heart        beats or units of time; and    -   a duty cycle of between about 5% and about 100%, e.g., 20%, in a        time frame of between about 5 seconds and several weeks, e.g.,        one day.

In some embodiments of the present invention, the control unit isconfigured to gradually ramp the commencement and/or termination ofstimulation. In order to achieve the gradual ramp, the control unit istypically configured to gradually modify one or more stimulationparameters, such as those described hereinabove, e.g., pulse amplitude,PPT, pulse frequency, pulse width, “on” time, and/or “off” time. Asappropriate, one or more of these parameters are varied by less than 50%of a pre-termination value per heart beat, in order to achieve thegradual ramp. For example, stimulation at 5 PPT may be graduallyterminated by reducing the PPT by 1 pulse per hour. Alternatively, oneor more of the parameters are varied by less than 5% per heart beat, inorder to achieve the gradual ramp. Terminating stimulation gradually,rather than suddenly, may reduce the likelihood of a reboundacceleration of heart rate that sometimes occurs upon termination ofvagal stimulation. For some applications, the control unit is configuredto gradually increase the strength of stimulation according to apredetermined schedule. Such a gradual increase is typically appropriateduring the first several days of use of the stimulation system by a newsubject, and/or when changing from one mode of operation to a differentmode of operation. For example, the strength of stimulation may beincreased less than 50% per hour, or less than 10% per day.

In some embodiments of the present invention, the control unit isconfigured to store a series of one or more physiological parametersmeasured by the stimulation system, in response to receiving an externalcommand to store the parameters. This allows a physician to specifyprecisely when to begin recording the series, which enables thephysician to monitor acute changes in the subject. For example, in orderto test external and/or stimulation effects on heart rate, the physicianmay begin recording the series prior to: (a) instructing the subject tochange his position, (b) applying carotid massage to the subject, (c)adjusting stimulation and/or feedback parameters, and/or (d) applyingstimulation to the subject using stimulation parameters the physicianwould like to evaluate.

In some embodiments of the present invention, a subject's reaction tostimulation using the stimulation system is evaluated while the subjectexercises. For some applications, a physician initially sets stimulationparameters of the system while the subject is at rest with a relativelylow heart rate. The subject then performs the exercise, which increasesthe heart rate to a level the physician considers to be at least themaximum level the subject is likely to experience during normal dailyactivity. Using feedback, the control unit reacts to the increased heartrate by modifying one or more stimulation parameters to increase thelevel of stimulation. This increased level of stimulation represents themaximum stimulation likely to be applied to the subject during use ofthe system. Therefore, such stimulation is likely to produce the maximumpotential side effects of stimulation that the subject may experience.The physician evaluates the subject at this increased level ofstimulation in order to assess these side effects and the tolerance ofthe subject to stimulation by the system. Based on this evaluation, thephysician may modify the stimulation parameters, or make other decisionsregarding the subject's treatment.

In some embodiments of the present invention, for applications in whichthe control unit is configured to apply vagal stimulationintermittently, as described hereinabove, the control unit begins thestimulation with an “off” period, rather than with an “on” period. As aresult, a delay having the duration of an “off” period occurs prior tobeginning stimulation. Alternatively or additionally, whether or notconfigured to apply stimulation intermittently, the control unit isconfigured to delay beginning the application of stimulation for acertain time period after receiving an external command to apply thestimulation. For some applications, the length of the time period isdetermined responsive to the output of a pseudo-random number generator.The use of these delaying techniques generally reduces a subject'santicipation of any discomfort that he may associate with stimulation,and disassociates the sensations of stimulation from the physicianand/or an external control device such as a wand.

In some embodiments of the present invention, a method for facilitatingthe determination of vagal stimulation parameters comprises: (a)applying intermittent vagal stimulation, as described hereinabove,during a calibration period of time that includes a plurality ofdifferent naturally-occurring heart rates; (b) for each “on” period andeach “off” period, calculating an average heart rate during the period;and (c) segmenting the average heart rates during the “off” periods intoa plurality of heart rate ranges; and (d) separately evaluating theeffect of vagal stimulation on heart rates within each heart rate range,by calculating an average difference in average heart rate between “on”and “off” periods within the given heart rate range. This analysis isused to determine separate stimulation and feedback parameters for eachrange of heart rates.

In some embodiments of the present invention, a method for surgicallyimplanting an electrode device comprises placing the electrode devicearound a vagus nerve, introducing conductive solution (e.g., salinesolution) into the electrode device such that the solution is in contactwith both the electrodes and the nerve, and measuring an impedance ofthe electrodes during the implantation procedure. Such impedancemeasurement enables the surgeon to determine during the procedure (a)whether the electrodes are positioned appropriately, (b) whethersufficient conductive solution has been introduced into and remained inthe electrode device, (c) whether the electrodes are the correct sizefor the nerve, and (d) whether the electrodes are in good contact withthe nerve.

For some applications, parasympathetic stimulation of the vagus nerve isapplied responsive to one or more sensed physiological parameters orother parameters, such as heart rate, electrocardiogram (ECG), bloodpressure, indicators of cardiac contractility, cardiac output,norepinephrine concentration, baroreflex sensitivity, or motion of thesubject. For some applications, stimulation is applied in a closed-loopsystem in order to achieve and maintain a desired heart rate responsiveto one or more such sensed parameters.

“Vagus nerve,” and derivatives thereof, as used in the specification andthe claims, is to be understood to include portions of the left vagusnerve, the right vagus nerve, and branches of the vagus nerve such asthe superior cardiac nerve, superior cardiac branch, and inferiorcardiac branch. Similarly, stimulation of the vagus nerve is describedherein by way of illustration and not limitation, and it is to beunderstood that stimulation of other autonomic nerves, including nervesin the epicardial fat pads, for treatment of heart conditions or otherconditions, is also included within the scope of the present invention.

“Heart failure,” as used in the specification and the claims, is to beunderstood to include all forms of heart failure, including ischemicheart failure, non-ischemic heart failure, and diastolic heart failure.

There is therefore provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject; and    -   a control unit, adapted to drive the electrode device to apply a        current to the site intermittently during alternating “on” and        “off” periods, each of the “on” periods having an “on” duration        equal to between 1 and 10 seconds, and each of the “off” periods        having an “off” duration equal to at least 50% of the “on”        duration.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

For some applications, the control unit is adapted to configure the “on”duration to be equal to between 1 and 5 seconds. For some applications,the control unit is adapted to configure the “off” duration to be equalto at least 100% of the “on” duration.

For some applications, the control unit is adapted to drive theelectrode device to apply the current using a set of one or moreparameters, and set at least one duration selected from the listconsisting of: the “on” duration and the “off” duration, so as to reducea heart rate of the subject by at least 10% of a heart rate reductionachievable when current is applied continuously using the set ofparameters.

For some applications, the control unit is adapted to reduce a heartrate of the subject by at least 5%.

For some applications, the control unit is adapted to drive theelectrode device to apply the current using a set of one or moreparameters, and set at least one duration selected from the listconsisting of: the “on” duration and the “off” duration, so as to reduceside effects of the current application compared to side effects whencurrent is applied continuously using the set of parameters.

For some applications, the control unit is adapted to begin theintermittent driving of the electrode device during one of the “off”periods.

For some applications, the control unit is adapted to configure thecurrent to reduce a heart rate of the subject. Alternatively, thecontrol unit is adapted to configure the current to increase a heartrate of the subject. Further alternatively, the control unit is adaptedto configure the current to minimize an effect of the applying of thecurrent on a heart rate of the subject.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective bursts of pulses in each of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is configured to drive the electrode device to apply adesired number of pulses per time period by setting at least oneduration selected from the list consisting of: the “on” duration and the“off” duration. For some applications, the control unit is configured todrive the electrode device to apply a desired number of pulses percardiac cycle by setting at least one duration selected from the listconsisting of: the “on” duration and the “off” duration. For someapplications, the control unit is adapted to apply a desired overallnumber of pulses per cardiac cycle over a time period including “on” and“off” periods, by applying a calculated number of pulses per cardiaccycle only during the “on” periods, the calculated number equal to theproduct of (a) the desired overall number and (b) the quotient of (i)the “on” duration plus the “off” duration and (ii) the “on” duration.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 100        microseconds and 1 millisecond, and to have an amplitude of        between 0.1 and 4 milliamps,    -   configure each of the bursts to have a duration of between 1 and        60 milliseconds, and to contain between 1 and 5 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 1 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        delay following an R-wave of the subject, the delay having a        duration of between 100 and 700 milliseconds.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 200        microseconds and 5 milliseconds, and to have an amplitude of        between 0.5 and 5 milliamps,    -   configure each of the bursts to have a duration of between 0.2        and 40 milliseconds, and to contain between 1 and 10 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 2 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        variable delay following a P-wave of the subject, the delay        having a duration equal to between two-thirds and 90% of a        duration of a cardiac cycle of the subject.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject; and    -   a control unit, adapted to drive the electrode device to apply a        current to the site intermittently during alternating “high” and        “low” strength periods, the “high” strength greater than the        “low” strength, a duration of each of the “high” and “low”        strength periods being greater than 1 second.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

For some applications, the control unit is adapted to configure thecurrent such that the “high” strength has a greater amplitude than the“low” strength. For some applications, the control unit is adapted toconfigure the current to reduce a heart rate of the subject.Alternatively, the control unit is adapted to configure the current toincrease a heart rate of the subject. Further alternatively, the controlunit is adapted to configure the current to minimize an effect of theapplying of the current on a heart rate of the subject.

For some applications, the control unit is adapted to:

-   -   during the “high” and “low” strength periods, drive the        electrode device to apply the current in respective bursts of        pulses in each of a plurality of cardiac cycles of the subject,    -   configure each of the pulses to have a duration of between 100        microseconds and 1 millisecond, and to have an amplitude of        between 0.1 and 4 milliamps,    -   configure each of the bursts to have a duration of between 1 and        60 milliseconds, and to contain between 1 and 5 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 1 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        delay following an R-wave of the subject, the delay having a        duration of between 100 and 700 milliseconds.

For some applications, the control unit is adapted to set a duration ofeach of the “high” strength periods to be less than 30 seconds, such asless than 5 seconds. For some applications, the control unit is adaptedto set a duration of each of the “low” strength periods to be less than30 seconds, such as less than 5 seconds.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective bursts of pulses in each of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is adapted to drive the electrode device to apply a greaternumber of pulses per burst during the “high” strength periods thanduring the “low” strength periods.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 200        microseconds and 5 milliseconds, and to have an amplitude of        between 0.5 and 5 milliamps,    -   configure each of the bursts to have a duration of between 0.2        and 40 milliseconds, and to contain between 1 and 10 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 2 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        variable delay following a P-wave of the subject, the delay        having a duration equal to between two-thirds and 90% of a        duration of a cardiac cycle of the subject.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to drive the electrode device to apply a        current to the site capable of reducing a heart rate of the        subject by at least 5%, the control unit having a peak power        consumption of less than 1 watt.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject;    -   a sensing element, adapted to sense heart beats of the subject;        and    -   a control unit, adapted to drive the electrode device to apply a        current to the site intermittently during alternating “on” and        “off” periods, durations of which “on” and “off” periods are        expressed in units of sensed heart beats, each of the “on”        periods having an “on” duration equal to a first number of        sensed heart beats, and each of the “off” periods having an        “off” duration equal to a second number of sensed heart beats.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

For some applications, the electrode device includes one or moreelectrodes, and the sensing element includes at least one of theelectrodes.

For some applications, each “on” period includes between 1 and 30 sensedheart beats. For some applications, each “off” period includes between 5and 40 sensed heart beats, or between 40 and 300 sensed heart beats. Forsome applications, each “on” period includes exactly one sensed heartbeat, and each “off” period includes exactly one sensed heart beat.

For some applications, the control unit is adapted to drive theelectrode device to apply the current using a set of one or moreparameters, and set at least one duration selected from the listconsisting of: the “on” duration and the “off” duration, so as to reducea heart rate of the subject by at least 10% of a heart rate reductionachievable when current is applied continuously using the set ofparameters.

For some applications, the control unit is adapted to begin theintermittent driving of the electrode device during one of the “off”periods. For some applications, the control unit is adapted to configurethe current to reduce a heart rate of the subject. Alternatively, thecontrol unit is adapted to configure the current to increase a heartrate of the subject. Further alternatively, the control unit is adaptedto configure the current to minimize an effect of the applying of thecurrent on a heart rate of the subject.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective bursts of pulses in each of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is configured to drive the electrode device to apply adesired number of pulses per cardiac cycle by setting at least oneduration selected from the list consisting of: the “on” duration and the“off” duration.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 100        microseconds and 1 millisecond, and to have an amplitude of        between 0.1 and 4 milliamps,    -   configure each of the bursts to have a duration of between 1 and        60 milliseconds, and to contain between 1 and 5 pulses,        configure the pulses within each of the bursts to have a pulse        repetition interval of between 1 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        delay following an R-wave of the subject, the delay having a        duration of between 100 and 700 milliseconds.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 200        microseconds and 5 milliseconds, and to have an amplitude of        between 0.5 and 5 milliamps,    -   configure each of the bursts to have a duration of between 0.2        and 40 milliseconds, and to contain between 1 and 10 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 2 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        variable delay following a P-wave of the subject, the delay        having a duration equal to between two-thirds and 90% of a        duration of a cardiac cycle of the subject.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject;    -   a sensing element, adapted to sense heart beats of the subject;        and    -   a control unit, adapted to drive the electrode device to apply a        current to the site intermittently during alternating “on” and        “off” periods, durations of one of which type of periods is        expressed in units of sensed heart beats, and durations of        another of which type of periods is expressed in units of time.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

For some applications, the electrode device includes one or moreelectrodes, and the sensing element includes at least one of theelectrodes.

In an embodiment, the control unit is adapted to express the durationsof the “off” periods in units of sensed heart beats, and the durationsof the “on” periods in units of time. Alternatively, the control unit isadapted to express the durations of the “on” periods in units of sensedheart beats, and the durations of the “off” periods in units of time.

For some applications, each “on” period includes between 1 and 30 sensedheart beats. For some applications, each “off” period has a duration ofbetween 2 and 60 seconds.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to drive the electrode device to apply        to the site a current that increases a heart rate of the        subject.

For some applications, the control unit is adapted to drive theelectrode device to apply the current in respective bursts of pulses ineach of a plurality of cardiac cycles of the subject.

For some applications, the control unit is adapted to drive theelectrode device to apply the current intermittently during alternating“on” and “off” periods, each of the “on” periods having an “on” durationbetween 1 and 10 seconds, and each of the “off” periods having an “off”duration equal to at least 50% of the “on” duration. For someapplications, the control unit is adapted to drive the electrode deviceto apply the current intermittently during alternating “high” and “low”strength periods, the “high” strength greater than the “low” strength, aduration of each of the “high” and “low” strength periods being greaterthan 1 second.

In an embodiment, the apparatus includes a sensing element, adapted tosense a heart rate of the subject, and the control unit is adapted todrive the electrode device to apply the current when the heart rate isless than a threshold value. For some applications, the threshold valueis less than 80 beats per minute.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to drive the electrode device to apply        to the site a current that both increases a heart rate of the        subject when the heart rate is below a first value, and        decreases the heart rate when the heart rate is above a second        value.

For some applications, the first value is no more than 80 beats perminute. For some applications, the second value is at least 80 beats perminute.

For some applications, the control unit is adapted to drive theelectrode device to apply the current in respective bursts of pulses ineach of a plurality of cardiac cycles of the subject.

For some applications, the control unit is adapted to drive theelectrode device to apply the current intermittently during alternating“on” and “off” periods, each of the “on” periods having an “on” durationequal to between 1 and 10 seconds, and each of the “off” periods havingan “off” duration equal to at least 50% of the “on” duration. For someapplications, the control unit is adapted to drive the electrode deviceto apply the current intermittently during alternating “high” and “low”strength periods, the “high” strength greater than the “low” strength, aduration of each of the “high” and “low” strength periods being greaterthan 1 second.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a heart rate sensor, adapted to sense a heart rate of the        subject; and    -   a control unit, adapted to drive the electrode device to:        -   responsively to a determination that the heart rate is above            a first threshold value, apply to the site a reducing            current that reduces the heart rate, and        -   responsively to a determination that the heart rate is below            a second threshold value, apply to the site an increasing            current that increases the heart rate.

For some applications, the first threshold value is at least 80 beatsper minute. For some applications, the second threshold value is no morethan 80 beats per minute.

For some applications, the control unit is adapted to drive theelectrode device to apply (a) the reducing current in respective burstsof pulses in each of a plurality of cardiac cycles of the subject, and(b) the increasing current in respective bursts of pulses in each of aplurality of cardiac cycles of the subject.

For some applications, the control unit is adapted to drive theelectrode device to apply (a) the reducing current intermittently duringalternating “on” and “off” periods, each of the “on” periods having an“on” duration equal to between 1 and 10 seconds, and each of the “off”periods having an “off” duration equal to at least 50% of the “on”duration, and (b) the increasing current intermittently duringalternating “on” and “off” periods, each of the “on” periods having an“on” duration equal to between 1 and 10 seconds, and each of the “off”periods having an “off” duration equal to at least 50% of the “on”duration.

For some applications, the control unit is adapted to drive theelectrode device to apply (a) the reducing current intermittently duringalternating “high” and “low” strength periods, the “high” strengthgreater than the “low” strength, a duration of each of the “high” and“low” strength periods being greater than 1 second, and (b) theincreasing current intermittently during alternating “high” and “low”strength periods, the “high” strength greater than the “low” strength, aduration of each of the “high” and “low” strength periods being greaterthan 1 second.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the reducingcurrent to include a stimulating current, which is capable of inducingaction potentials in a first set and a second set of nerve fibers of thevagus nerve, and an inhibiting current, which is capable of inhibitingthe induced action potentials traveling in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set. For some applications,the control unit is adapted to configure the increasing current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set.

For some applications, the control unit is adapted to configure thereducing current to include a stimulating current, which is capable ofinducing action potentials in the vagus nerve, and an inhibitingcurrent, which is capable of inhibiting action potentials induced by thestimulating current and traveling in the vagus nerve in an afferentdirection toward a brain of the subject. For some applications, thecontrol unit is adapted to configure the increasing current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including intermittently applying acurrent to a site of a subject during alternating “on” and “off”periods, each of the “on” periods having an “on” duration between 1 and10 seconds, and each of the “off” periods having an “off” duration equalto at least 50% of the “on” duration.

There is still additionally provided, in accordance with an embodimentof the present invention, a method including intermittently applying acurrent to a site of a subject during alternating “high” and “low”strength periods, the “high” strength greater than the “low” strength, aduration of each of the “high” and “low” strength periods being greaterthan 1 second.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   applying to a site of a subject a current capable of reducing a        heart rate of the subject by at least 5%; and    -   consuming, while at peak power consumption, less than 1 watt        while applying the current,    -   the site selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

-   -   sensing heart beats of a subject; and    -   intermittently applying a current to a site of the subject        during alternating “on” and “off” periods, durations of which        “on” and “off” periods are expressed in units of sensed heart        beats, each of the “on” periods having an “on” duration equal to        a first number of sensed heart beats, and each of the “off”        periods having an “off” duration equal to a second number of        sensed heart beats.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   sensing heart beats of a subject; and    -   intermittently applying a current to a site of the subject        during alternating “on” and “off” periods, durations of one of        which type of periods is expressed in units of sensed heart        beats, and durations of another of which type of periods is        expressed in units of time.

There is still further provided, in accordance with an embodiment of thepresent invention, a method including applying to a site of a subject acurrent that increases a heart rate of the subject, the site selectedfrom the list consisting of: a vagus nerve of the subject, an epicardialfat pad of the subject, a pulmonary vein of the subject, a carotidartery of the subject, a carotid sinus of the subject, a coronary sinusof the subject, a vena cava vein of the subject, a right ventricle ofthe subject, and a jugular vein of the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including applying to a site of a subject acurrent that both increases a heart rate of the subject when the heartrate is below a first value, and decreases the heart rate when the heartrate is above a second value, the site selected from the list consistingof: a vagus nerve of the subject, an epicardial fat pad of the subject,a pulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   sensing a heart rate of a subject;    -   responsively to a determination that the heart rate is above a        first threshold value, applying to a site of the subject a        reducing current that reduces the heart rate, the site selected        from the list consisting of: a vagus nerve of the subject, an        epicardial fat pad of the subject, a pulmonary vein of the        subject, a carotid artery of the subject, a carotid sinus of the        subject, a coronary sinus of the subject, a vena cava vein of        the subject, a right ventricle of the subject, and a jugular        vein of the subject; and    -   responsively to a determination that the heart rate is below a        second threshold value, applying to the site an increasing        current that increases the heart rate.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a control unit, adapted to be implanted in the subject, and to        drive the electrode device to apply an electrical current to the        site; and    -   an external monitoring unit, adapted to be positioned external        to a body of the subject, and to record timing of the        application of the current.

For some applications, the control unit is adapted to drive theelectrode device to apply the current to the site intermittently duringalternating “on” and “off” periods, each of the “on” periods having an“on” duration equal to at least 1 second, and each of the “off” periodshaving an “off” duration equal to at least 50% of the “on” duration, andthe monitoring unit is adapted to record the timing of at least one typeof period selected from the list consisting of “on” and “off” periods.

For some applications, the monitoring unit is adapted to record thetiming in real time. For some applications, the control unit is adaptedto transmit a communication signal to the external monitoring unit eachtime the control unit drives the electrode device to apply the currentto the site.

In an embodiment, the apparatus includes an electrocardiogram (ECG)monitor, and the monitoring unit is adapted to record the timing bydetecting an artifact in the ECG that is indicative of the applicationof the current. For some applications, the control unit is adapted todrive the electrode device to apply the current synchronized with afeature of the ECG, and the monitoring unit is adapted to detect theartifact only at a known time of current application with respect to thefeature of the ECG. For some applications, the ECG monitor is configuredto assign a dedicated recording channel thereof to record electricalpotential differences between two sides of a neck of the subject, andthe monitoring unit is adapted to detect the current application byanalyzing the dedicated recording channel.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   applying an electrical current to a site of a subject selected        from the list consisting of: a vagus nerve of the subject, an        epicardial fat pad of the subject, a pulmonary vein of the        subject, a carotid artery of the subject, a carotid sinus of the        subject, a coronary sinus of the subject, a vena cava vein of        the subject, a right ventricle of the subject, and a jugular        vein of the subject; and    -   recording, from a location external to the subject, timing of        the application of the current.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site a current in            respective bursts of pulses in each of a plurality of            cardiac cycles of the subject, and        -   count a number of pulses applied to the site.

For some applications, the control unit is adapted to drive theelectrode device to apply the current intermittently during alternating“on” and “off” periods, each of the “on” periods having an “on” durationequal to between 1 and 10 seconds, and each of the “off” periods havingan “off” duration equal to at least 50% of the “on” duration.

For some applications, the control unit is adapted to configure thecurrent so as to reduce a heart rate of the subject. Alternatively, thecontrol unit is adapted to configure the current so as to increase aheart rate of the subject. Further alternatively, the control unit isadapted to configure the current so as to minimize an effect of theapplying of the current on a heart rate of the subject.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 100        microseconds and 1 millisecond, and to have an amplitude of        between 0.1 and 4 milliamps,    -   configure each of the bursts to have a duration of between 1 and        60 milliseconds, and to contain between 1 and 5 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 1 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        delay following an R-wave of the subject, the delay having a        duration of between 100 and 700 milliseconds.

For some applications, the control unit is adapted to:

-   -   configure each of the pulses to have a duration of between 200        microseconds and 5 milliseconds, and to have an amplitude of        between 0.5 and 5 milliamps,    -   configure each of the bursts to have a duration of between 0.2        and 40 milliseconds, and to contain between 1 and 10 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 2 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        variable delay following a P-wave of the subject, the delay        having a duration equal to between two-thirds and 90% of a        duration of a cardiac cycle of the subject.

In an embodiment, the control unit is adapted to count the number ofpulses applied to the site during a period of time, count a number ofbursts applied to the site during the period, and calculate an averagenumber of pulses per burst by dividing the number of pulses countedduring the period by the number of bursts counted during the period. Forsome applications, the control unit is adapted to modify a parameterresponsively to the average number of pulses per burst, the parameterselected from the list consisting of: a parameter of the current, and aparameter of a feedback algorithm used by the control unit.

For some applications, the control unit is adapted to determine whetherthe average number of pulses per burst crosses a threshold value, and,responsively to such a determination, to modify at least one parameterto an extent necessary to cause the average number of pulses per burstto no longer cross the threshold value, the parameter selected from thelist consisting of: a parameter of the current, and a parameter of afeedback algorithm used by the control unit. For some applications, thethreshold value is between 2 and 4 pulses per burst, and the controlunit is adapted to determine whether the average number of pulses perburst exceeds the threshold value.

In an embodiment, the apparatus includes a sensing element, adapted tosense heart beats of the subject, and the control unit is adapted tocount a number of bursts applied to the site during a period of time,and count a number of heart beats sensed during the period. For someapplications, the control unit is adapted to calculate an average numberof bursts per heart beat by dividing the number of bursts counted duringthe period by the number of heart beats counted during the period. Forsome applications, the control unit is adapted to modify a parameterresponsively to the average number of bursts per heart beat, theparameter selected from the list consisting of: a parameter of thecurrent, and a parameter of a feedback algorithm used by the controlunit. For some applications, the control unit is adapted to determinewhether the average number of bursts per heart beat crosses a thresholdvalue, and, responsively to such a determination, to modify at least oneparameter to an extent necessary to cause the average number of burstsper heart beat to no longer cross the threshold value, the parameterselected from the list consisting of: a parameter of the current, and aparameter of a feedback algorithm used by the control unit.

For some applications, the control unit is adapted to count the numberof pulses applied to the site during the period, and calculate anaverage number of pulses per burst by dividing the number of pulsescounted during the period by the number of bursts counted during theperiod.

In an embodiment, the apparatus includes a sensing element, adapted tosense heart beats of the subject, and the control unit is adapted tocount a number of pulses applied to the site during a period of time,and count a number of heart beats sensed during the period. For someapplications, the control unit is adapted to count a number of burstsapplied to the site during the period, and calculate an average numberof pulses per burst by dividing the number of pulses counted during theperiod by the number of bursts counted during the period. For someapplications, the control unit is adapted to calculate an average numberof pulses per heart beat by dividing the number of pulses counted duringthe period by the number of heart beats counted during the period. Forsome applications, the control unit is adapted to modify a parameter ofthe current responsively to the average number of pulses per heart beat.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a sensing element, adapted to sense a physiological parameter of        the subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply a current to the site,        -   configure a parameter of the current responsively to the            sensed physiological parameter,        -   calculate an average of the current parameter, over a period            of time having a duration of at least 1 minute, and        -   regulate the current parameter such that the average of the            current parameter does not exceed a maximum current            parameter level regardless of the sensed physiological            parameter.

For some applications, the control unit is adapted to regulate thecurrent parameter by modifying a parameter of a feedback algorithm usedby the control unit.

For some applications, the control unit is adapted to regulate thecurrent parameter by driving the electrode device to apply the currentintermittently during alternating “on” and “off” periods, each of the“on” periods having an “on” duration equal to at least 1 second, andeach of the “off” periods having an “off” duration equal to at least 50%of the “on” duration.

For some applications, the control unit is adapted to generate anexternal notification signal if the average of the current parameterwould exceed the maximum current parameter in the absence of theregulating of the current parameter.

For some applications, the control unit is adapted to express themaximum current parameter as a number of contiguous heart beats duringwhich the current is applied. Alternatively, the control unit is adaptedto express the maximum current parameter as a time period of continuouscurrent application. Further alternatively, the control unit is adaptedto express the maximum current parameter as an average amount of energyapplied over a time period.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective bursts of pulses in each of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is adapted to express the maximum current parameter as theproduct of (a) pulses per burst and (b) amplitude of the current over atime period. For some applications, the control unit is adapted toexpress the maximum current parameter level in pulses per burst. Forsome applications, the maximum current parameter is between 2 and 20pulses per burst.

For some applications, the control unit is adapted to express themaximum current parameter as a duty cycle over a time period of between5 seconds and 3 weeks. For some applications, the duty cycle is between5% and 100%.

For some applications, the control unit is adapted to express themaximum current parameter as power over a time period of between 5seconds and 3 weeks. For some applications, the maximum currentparameter is less than 1 watt.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a sensing element, adapted to sense a physiological parameter of        the subject;    -   an input element, adapted to receive a command generated        external to the apparatus; and    -   a control unit, which includes a memory, the control unit        adapted to:        -   drive the electrode device to apply a current to the site,            and        -   in response to receiving the command, store in the memory            the physiological parameter sensed at a plurality of points            in time.

For some applications, the control unit is adapted to begin storing thephysiological parameter sensed at the plurality of points in time, aftera delay from a time of receiving the command.

For some applications, the plurality of points in time includes apredetermined number of points in time, and the control unit is adaptedto store the physiological parameter sensed at the points in time.

For some applications, the physiological parameter includes an R-Rinterval of the subject, and the sensing element is adapted to sense theR-R interval. Alternatively or additionally, the physiological parameterincludes systolic and diastolic blood pressures of the subject, and thesensing element is adapted to sense the blood pressures. Furtheralternatively or additionally, the physiological parameter includes atleast one feature of an electrocardiogram (ECG) of the subject, and thesensing element includes an ECG monitor.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   an input element, adapted to receive an apparatus activation        command generated external to the apparatus; and    -   a control unit, adapted to begin driving the electrode device to        apply a current to the site, responsively to receiving the        activation command, after a delay of at least 5 seconds from a        time of receiving the activation command.

For some applications, the control unit is adapted to apply the currentintermittently during alternating “on” and “off” periods, each of the“on” periods having an “on” duration equal to at least 1 second, andeach of the “off” periods having an “off” duration equal to at least 50%of the “on” duration, a duration of the delay is equal to a duration ofa single one of the “off” periods, and the control unit is adapted tobegin driving the current after the delay by beginning the intermittentapplication of the current during one of the “off” periods.

For some applications, the control unit includes a pseudo-random numbergenerator, and the control unit is adapted to set a length of the delayat least in part responsively to an output of the pseudo-random numbergenerator.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a heart rate sensor, adapted to sense a heart rate of the        subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site a current,            and        -   configure the current responsively to a comparison of (a)            the sensed heart rate and (b) a target heart rate that is a            function of an average heart rate of the subject.

For some applications, the control unit is adapted to determine thetarget heart rate in real time. For some applications, the control unitis configured to determine the average heart rate of the subjectresponsively to the sensed heart rate of the subject. For someapplications, the control unit is adapted to calculate the average heartrate over a period of between 12 hours and 2 weeks. For someapplications, the control unit is adapted to calculate the average heartrate over a period of between 10 minutes and 24 hours.

For some applications, the control unit is adapted to set the targetheart rate equal to the average heart rate. For some applications, thecontrol unit is adapted to set the target heart rate to a value within5% of the average heart rate.

For some applications, the control unit is adapted to determine theaverage heart rate and the target heart rate in real time. For someapplications, the control unit is adapted to determine the average heartrate over a recent time period that ends less than 1 hour prior to thedetermination. For some applications, the control unit is adapted todetermine the average heart rate when the subject is at rest.

For some applications, the control unit is adapted to configure thecurrent so as to reduce the sensed heart rate towards the target heartrate. Alternatively, the control unit is adapted to configure thecurrent so as to increase the sensed heart rate towards the target heartrate.

For some applications, the control unit is adapted to:

-   -   drive the electrode device to apply the current in respective        bursts of pulses in each of a plurality of cardiac cycles of the        subject,    -   configure each of the pulses to have a duration of between 100        microseconds and 1 millisecond, and to have an amplitude of        between 0.1 and 4 milliamps,    -   configure each of the bursts to have a duration of between 1 and        60 milliseconds, and to contain between 1 and 5 pulses,    -   configure the pulses within each of the bursts to have a pulse        repetition interval of between 1 and 10 milliseconds, and    -   drive the electrode device to apply each of the bursts after a        delay following an R-wave of the subject, the delay having a        duration of between 100 and 700 milliseconds.

For some applications, the control unit is adapted to set the targetheart rate greater than the average heart rate, such as equal to 15%greater than the average heart rate.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site a current            that changes a heart rate of the subject, and        -   gradually modify at least one parameter of the current by            less than a percentage selected from the list consisting of:            50% of a pre-termination value per heart beat of the            subject, and 5% per heart beat of the subject, until the            parameter reaches a desired value, during a transitional            period selected from the list consisting of: a commencement            of stimulation period, and a termination of stimulation            period.

For some applications, the control unit is adapted to gradually modifythe parameter during the transitional period, which transitional periodincludes the commencement of stimulation period and has a duration of atleast 24 hours, such that a level of vagal stimulation caused by thecurrent gradually increases.

For some applications, the control unit is adapted to gradually modifythe parameter according to a predetermined schedule.

For some applications, the control unit is adapted to gradually modifythe parameter by less than 50% per hour. For some applications, thecontrol unit is adapted to gradually modify the parameter by less than10% per 24-hour period.

For some applications, the percentage is 50% of the pre-terminationvalue per heart beat. For some applications, the percentage is 5% perheart beat.

For some applications, the parameter includes an amplitude of thecurrent, and the control unit is adapted to gradually modify theamplitude.

For some applications, the control unit is adapted to drive theelectrode device to apply the current intermittently during alternating“on” and “off” periods, each of the “on” periods having an “on” durationequal to at least 1 second, and each of the “off” periods having an“off” duration equal to at least 50% of the “on” duration, the parameteris selected from the list consisting of: a duration of each of the “on”periods, and a duration of each of the “off” periods, and the controlunit is adapted to gradually modify the selected parameter.

For some applications, the control unit is adapted to drive theelectrode device to apply the current in respective bursts of pulses ineach of a plurality of cardiac cycles of the subject. For someapplications, the parameter is selected from the list consisting of:pulses per burst, pulse frequency, and pulse width, and the control unitis adapted to gradually modify the selected parameter.

In an embodiment, the apparatus includes an input element, adapted toreceive one or more commands generated external to the apparatus, andthe control unit is adapted to gradually modify the parameter at leastin part responsively to the commands. For some applications, thecommands include a request to return to a previous level of currentapplication, and the control unit is adapted to set the parameter at aprevious value of the parameter responsively to the commands.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject;    -   a heart rate sensor, adapted to sense a heart rate of the        subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site a current in            respective bursts of pulses in each of a plurality of            cardiac cycles of the subject,        -   set a number of pulses in each of the bursts, using a            feedback algorithm that includes as an input thereto the            sensed heart rate, and        -   modify at least one parameter if an average number of pulses            per burst crosses a threshold value, the parameter selected            from the list consisting of: a parameter of the current, and            a parameter of the feedback algorithm.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

For some applications, the parameter of the feedback algorithm includesa target heart rate, and the control unit is adapted to modify thetarget heart rate if the average number of pulses per burst crosses thethreshold value. For some applications, the parameter of the feedbackalgorithm includes an integral slope of the feedback algorithm, and thecontrol unit is adapted to modify the integral slope if the averagenumber of pulses per burst crosses the threshold value.

For some applications, the parameter of the current includes anamplitude of the current, and the control unit is adapted to modify theamplitude if the average number of pulses per burst crosses thethreshold value. For some applications, the parameter of the currentincludes a duration of each of the pulses, and the control unit isadapted to modify the pulse duration if the average number of pulses perburst crosses the threshold value. For some applications, the parameterof the current includes a maximum number of pulses per burst, and thecontrol unit is adapted to modify the maximum number of pulses per burstif the average number of pulses per burst crosses the threshold value.

For some applications, the threshold value is between 2 and 4 pulses perburst, such as 3 pulses per burst.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject;    -   a heart rate sensor, adapted to sense a heart rate of the        subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site electrical            stimulation in respective bursts in each of a plurality of            cardiac cycles of the subject, each of the bursts including            one or more pulses,        -   set at least one primary parameter of the stimulation, using            a feedback algorithm that includes as an input thereto the            sensed heart rate, and        -   modify at least one secondary parameter if an average duty            cycle of the stimulation crosses a threshold value, the            secondary parameter selected from the list consisting of: a            parameter of the stimulation, and a parameter of the            feedback algorithm.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

In an embodiment, the secondary parameter includes the primaryparameter, and the control unit is adapted to modify the at least oneprimary parameter if the average duty cycle crosses the threshold value.

For some applications, the secondary parameter includes a target heartrate, and the control unit is adapted to modify the target heart rate ifthe average duty cycle of the stimulation crosses the threshold value.For some applications, the secondary parameter includes an integralslope of the feedback algorithm, and the control unit is adapted tomodify the integral slope if the average duty cycle of the stimulationcrosses the threshold value.

For some applications, the secondary parameter includes an amplitude ofthe current, and the control unit is adapted to modify the amplitude ifthe average duty cycle of the stimulation crosses the threshold value.For some applications, the secondary parameter includes a duration ofeach of the pulses, and the control unit is adapted to modify the pulseduration if the average duty cycle of the stimulation crosses thethreshold value. For some applications, the secondary parameter includesa maximum number of pulses per burst, and the control unit is adapted tomodify the maximum number if the average duty cycle of the stimulationcrosses the threshold value.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the control unit is adapted to configure the current toinclude a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set. For some applications, thecontrol unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject;    -   a heart rate sensor, adapted to sense a heart rate of the        subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site,            intermittently during alternating “on” and “off” periods,            electrical stimulation capable of lowering the heart rate,            the stimulation having a duty cycle expressed as a number of            stimulations per heart beat, and each of the “on” periods            having an “on” duration equal to at least 1 second, and each            of the “off” periods having an “off” duration equal to at            least 50% of the “on” duration,        -   responsively to the sensed heart rate, set at least one            parameter of the stimulation, and        -   determine a magnitude of a heart-rate-lowering effect of the            stimulation by comparing an aspect of each “on” period to an            aspect of each “off” period.

In an embodiment, the site is selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject, and the electrode device is adapted to becoupled to the selected site.

For some applications, the control unit is adapted to determine apresence of the heart-rate-lowering effect.

For some applications, the aspect of each “on” period includes aduration of each “on” period, and the aspect of each “off” periodincludes a duration of each “off” period, and the control unit isadapted to determine the magnitude by comparing (a) a ratio of theduration of each “on” period to the duration of each “off” period, to(b) the duty cycle of the stimulation. For some applications, thecontrol unit is adapted to interpret the duty cycle being less than theratio as indicative of a presence of the heart-rate-lowering effect. Forsome applications, the control unit is adapted to make the determinationbased on the duty cycle over a time period that includes at least onefull “on” period and one full “off” period.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a heart rate sensor, adapted to sense a heart rate of the        subject; and    -   a control unit, adapted to:        -   drive the electrode device to apply electrical stimulation            to the site, and        -   configure the stimulation to have a strength that is            inversely related to the sensed heart rate.

In an embodiment, the control unit is adapted to configure thestimulation to have a strength that is inversely proportional to thesensed heart rate.

For some applications, the control unit is adapted to drive theelectrode device to apply the stimulation when the subject is sleeping.

For some applications, the control unit is adapted to drive theelectrode device to apply the stimulation intermittently duringalternating “on” and “off” periods, each of the “on” periods having an“on” duration equal to between 1 and 10 seconds, and each of the “off”periods having an “off” duration equal to at least 50% of the “on”duration.

In an embodiment, the control unit is adapted to withhold driving theelectrode device to apply the stimulation when the sensed heart rateexceeds a threshold value. For some applications, the threshold value isgreater than 50 beats per minute. For some applications, the thresholdvalue is less than an average heart rate of the subject. For someapplications, the threshold value equals the average heart rate minus acertain number of beats per minute. For some applications, the thresholdvalue equals the average heart rate minus a certain number of standarddeviations, such as at least one standard deviation. For someapplications, the threshold value equals the average heart rate minus acertain percentage of the heart rate, such as between 1% and 40%.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the stimulation in respective bursts of pulses in eachof a plurality of cardiac cycles of the subject. In an embodiment, theelectrode device is adapted to be coupled to a left vagus nerve of thesubject. For some applications, the control unit is adapted to configureeach of the pulses to have a duration of between 200 microseconds and2.5 milliseconds. For some applications, the control unit is adapted toconfigure each of the pulses to have a duration of between 2.5 and 5milliseconds. For some applications, the control unit is adapted toconfigure each of the bursts to have a duration of between 0.2 and 40milliseconds. For some applications, the control unit is adapted toconfigure each of the bursts to contain between 1 and 10 pulses. Forsome applications, the control unit is adapted to configure the pulseswithin each of the bursts to have a pulse repetition interval of between2 and 10 milliseconds. For some applications, the control unit isadapted to configure the pulses to have an amplitude of between 0.5 and5 milliamps.

For some applications, the control unit is adapted to drive theelectrode device to apply the bursts less than every heartbeat of thesubject. Alternatively, the control unit is adapted to drive theelectrode device to apply the bursts once per heartbeat of the subject.

For some applications, the control unit is adapted to drive theelectrode device to apply the stimulation to the site intermittentlyduring alternating “on” and “off” periods, each of the “on” periodshaving a duration of at least 1 second.

For some applications, the control unit is adapted to drive theelectrode device to apply each of the bursts after a variable delayfollowing a P-wave of the subject, the delay having a duration equal tobetween two-thirds and 90% of a duration of a cardiac cycle of thesubject.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a sleep detector, adapted to generate a signal indicative of        sleeping by the subject; and    -   a control unit, adapted to drive the electrode device to apply a        current to the site, responsively to receiving the signal.

For some applications, the sleep detector includes an accelerometer, anelectroencephalogram (EEG) device, and/or a clock.

For some applications, the control unit is adapted to configure thecurrent so as to reduce a heart rate of the subject. Alternatively, thecontrol unit is adapted to configure the current so as to minimize aneffect of the applying of the current on a heart rate of the subject.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   applying to a site of a subject a current in respective bursts        in each of a plurality of cardiac cycles of the subject, each of        the bursts including two or more pulses, the site selected from        the list consisting of: a vagus nerve of the subject, an        epicardial fat pad of the subject, a pulmonary vein of the        subject, a carotid artery of the subject, a carotid sinus of the        subject, a coronary sinus of the subject, a vena cava vein of        the subject, a right ventricle of the subject, and a jugular        vein of the subject; and    -   counting a number of pulses applied to the site.

There is still further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   sensing a physiological parameter of a subject;    -   applying a current to a site of the subject selected from the        list consisting of: a vagus nerve of the subject, an epicardial        fat pad of the subject, a pulmonary vein of the subject, a        carotid artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and a jugular vein of the        subject;    -   configuring a parameter of the current responsively to the        sensed physiological parameter;    -   calculating an average of the current parameter, over a period        of time having a duration of at least 1 minute; and    -   regulating the current parameter such that the average of the        current parameter does not exceed a maximum current parameter        level regardless of the sensed physiological parameter.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   sensing a physiological parameter of a subject;    -   applying a current to a site of the subject selected from the        list consisting of: a vagus nerve of the subject, an epicardial        fat pad of the subject, a pulmonary vein of the subject, a        carotid artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and a jugular vein of the        subject;    -   receiving a command from a location outside of a body of the        subject; and    -   in response to receiving the command, storing the physiological        parameter sensed at a plurality of points in time.

For some applications, the method includes generating the command, andsubsequently instructing the subject to change a position of thesubject. For some applications, the method includes generating thecommand, and subsequently applying carotid massage to the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   receiving an activation command from a location outside of a        body of a subject; and    -   beginning to apply a current to a site of the subject,        responsively to receiving the activation command, after a delay        of at least 5 seconds from a time of receiving the activation        command, the site selected from the list consisting of: a vagus        nerve of the subject, an epicardial fat pad of the subject, a        pulmonary vein of the subject, a carotid artery of the subject,        a carotid sinus of the subject, a coronary sinus of the subject,        a vena cava vein of the subject, a right ventricle of the        subject, and a jugular vein of the subject.

There is still additionally provided, in accordance with an embodimentof the present invention, a method including:

-   -   sensing a heart rate of a subject;    -   applying a current to a site of the subject selected from the        list consisting of: a vagus nerve of the subject, an epicardial        fat pad of the subject, a pulmonary vein of the subject, a        carotid artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and ajugular vein of the        subject; and    -   configuring the current responsively to a comparison of (a) the        sensed heart rate and (b) a target heart rate that is a function        of an average heart rate of the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   applying to a site of a subject a current that changes a heart        rate of the subject, the site selected from the list consisting        of: a vagus nerve of the subject, an epicardial fat pad of the        subject, a pulmonary vein of the subject, a carotid artery of        the subject, a carotid sinus of the subject, a coronary sinus of        the subject, a vena cava vein of the subject, a right ventricle        of the subject, and a jugular vein of the subject; and    -   gradually modifying at least one parameter of the current by        less than a percentage selected from the list consisting of: 50%        of a pre-termination value per heart beat of the subject, and 5%        per heart beat of the subject, until the parameter reaches a        desired value, during a transitional period selected from the        list consisting of: a commencement of stimulation period, and a        termination of stimulation period.

There is still additionally provided, in accordance with an embodimentof the present invention, a method including:

-   -   sensing a heart rate of a subject;    -   applying to a site of the subject a current in respective bursts        in each of a plurality of cardiac cycles of the subject, each of        the bursts including one or more pulses;    -   setting a number of pulses in each of the bursts, using a        feedback algorithm that includes as an input thereto the sensed        heart rate; and    -   modifying at least one parameter if an average number of pulses        per burst crosses a threshold value, the parameter selected from        the list consisting of: a parameter of the current, and a        parameter of the feedback algorithm.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   sensing a heart rate of a subject;    -   applying to a site of the subject electrical stimulation in        respective bursts in each of a plurality of cardiac cycles of        the subject, each of the bursts including one or more pulses;    -   setting at least one primary parameter of the stimulation, using        a feedback algorithm that includes as an input thereto the        sensed heart rate; and    -   modifying at least one secondary parameter if an average duty        cycle of the stimulation crosses a threshold value, the        secondary parameter selected from the list consisting of: a        parameter of the stimulation, and a parameter of the feedback        algorithm.

There is still additionally provided, in accordance with an embodimentof the present invention, a method including:

-   -   sensing a heart rate of a subject;    -   applying to a site of the subject intermittently during        alternating “on” and “off” periods, electrical stimulation        capable of lowering the heart rate, the stimulation having a        duty cycle expressed as a number of stimulations per heart beat,        and each of the “on” periods having an “on” duration equal to at        least 1 second, and each of the “off” periods having an “off”        duration equal to at least 50% of the “on” duration;    -   responsively to the sensed heart rate, setting at least one        parameter of the stimulation; and    -   determining a magnitude of a heart-rate-lowering effect of the        stimulation by comparing an aspect of each “on” period to an        aspect of each “off” period.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   sensing a heart rate of a subject;    -   applying electrical stimulation to a site of the subject        selected from the list consisting of: a vagus nerve of the        subject, an epicardial fat pad of the subject, a pulmonary vein        of the subject, a carotid artery of the subject, a carotid sinus        of the subject, a coronary sinus of the subject, a vena cava        vein of the subject, a right ventricle of the subject, and a        jugular vein of the subject; and    -   configuring the stimulation to have a strength that is inversely        related to the sensed heart rate.

There is also provided, in accordance with an embodiment of the presentinvention, a method including:

-   -   detecting sleeping by a subject; and    -   responsively to detecting the sleeping, applying a current to a        site of the subject selected from the list consisting of: a        vagus nerve of the subject, an epicardial fat pad of the        subject, a pulmonary vein of the subject, a carotid artery of        the subject, a carotid sinus of the subject, a coronary sinus of        the subject, a vena cava vein of the subject, a right ventricle        of the subject, and a jugular vein of the subject.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   applying a current to a site of a subject selected from the list        consisting of: a vagus nerve of the subject, an epicardial fat        pad of the subject, a pulmonary vein of the subject, a carotid        artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and a jugular vein of the        subject;    -   sensing a first physiological parameter of the subject;    -   configuring a parameter of the current responsively to the first        physiological parameter;    -   while the subject is exercising, sensing a second physiological        parameter of the subject at a plurality of different exercise        levels of exertion of the subject; and    -   determining a tolerance of the subject to the application of the        current by analyzing the second physiological parameter at the        plurality of different exercise levels.

For some applications, applying the current includes applying thecurrent during a plurality of time periods, and configuring at least oneparameter of the current to have a different value during each of thetime periods, and sensing the second physiological parameter includessensing the second physiological parameter during the plurality of timeperiods.

For some applications, the method includes configuring the currentresponsively to determining the tolerance.

For some applications, a first one of the different exercise levels ofexertion includes a resting level of exertion, and sensing the secondphysiological parameter includes sensing the second physiologicalparameter at the first exercise level. For some applications, a firstone of the different exercise levels of exertion includes a recoveryfrom exercise level of exertion, and sensing the second physiologicalparameter includes sensing the second physiological parameter at thefirst exercise level.

For some applications; the method includes adjusting the parameter ofthe current so as to achieve a heart rate of the subject at which theheart is maximally effective.

In an embodiment, the site includes the vagus nerve, and applying thecurrent includes applying the current to the vagus nerve.

For some applications, the first physiological parameter includes aheart rate of the subject, and configuring the parameter of the currentincludes configuring the parameter of the current responsively to theheart rate of the subject. For some applications, configuring theparameter includes increasing a strength of the current responsively toan increase in the heart rate.

There is still further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   applying a current to a site of a subject selected from the list        consisting of: a vagus nerve of the subject, an epicardial fat        pad of the subject, a pulmonary vein of the subject, a carotid        artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and a jugular vein of the        subject;    -   while the subject is exercising, sensing, at a plurality of        different exercise levels of exertion of the subject, a        physiological parameter of the subject indicative of an        effectiveness of a heart of the subject; and    -   responsively to the physiological parameter, configuring a        parameter of the current to change a heart rate of the subject        to a rate at which the effectiveness increases.

For some applications, applying the current includes applying thecurrent during a plurality of time periods, and configuring theparameter of the current to have a different value during each of thetime periods.

In an embodiment, the site includes the vagus nerve, and applying thecurrent includes applying the current to the vagus nerve.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   during a calibration period of time that includes a plurality of        different naturally-occurring heart rates of a subject,        intermittently applying a calibration current to a site of the        subject during a plurality of alternating “on” and “off”        periods, each of the “on” periods having an “on” duration equal        to at least 1 second, and each of the “off” periods having an        “off” duration equal to at least 50% of the “on” duration,    -   the site selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   sensing a heart rate of the subject during the calibration        period; and    -   for each of two or more of the “on” periods, plotting a point on        a graph, a first coordinate of the point indicative of an “on”        average heart rate of the subject during the “on” period, and a        second coordinate of the point indicative of an “off” average        heart rate during at least one of: the “off” period immediately        preceding the “on” period, and the “off” period immediately        following the “on” period.

For some applications, applying the calibration current includessubjecting the subject to an exercise test during at least a portion ofthe calibration period.

For some applications, plotting the point includes expressing the “on”and “off” average heart rates as R-R intervals.

For some applications, the first and second coordinates are y- andx-coordinates of the point, respectively, and the method includesinterpreting that the point lies above a line defined by x=y as anindication that the “on” average heart rate is less than the “off”average heart rate for the point.

For some applications, applying the calibration current includes:

-   -   subjecting the subject to an exercise test during at least a        first portion of the calibration period;    -   instructing the subject to relax during at least a second        portion of the calibration period; and    -   instructing the subject to rest during at least a third portion        of the calibration period.

For some applications, each of the “on” periods has a duration ofbetween 45 and 75 seconds, and each of the “off” periods has a durationof between 90 and 150 seconds. For some applications, the calibrationperiod includes at least 200 “on” periods and at least 200 “off”periods. For some applications, the calibration period has a duration ofat least 24 hours.

In an embodiment, the site includes the vagus nerve, and applying thecalibration current includes applying the current to the vagus nerve.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an implantable sensor, adapted to sense an electrical parameter        of a heart of a subject;    -   a first control unit, adapted to apply pulses to the heart        responsively to the sensed parameter, the pulses selected from        the list consisting of: pacing pulses and anti-arrhythmic        energy;    -   an electrode device, adapted to be coupled to a site of the        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a second control unit, adapted to drive the electrode device to        apply to the site a current that increases parasympathetic tone        of the subject and affects a heart rate of the subject,    -   wherein the first and second control units are not under common        control, and    -   wherein at least one of the control units is adapted to        coordinate an aspect of its operation with an aspect of        operation of the other control unit.

In an embodiment, the second control unit is adapted to generate acommunication signal indicative of driving the electrode device to applythe current, and the first control unit is adapted to receive thecommunication signal, and to regulate an aspect of its own operationresponsively to receiving the communication signal.

For some applications, the second control unit is adapted to configurethe current to reduce the heart rate of the subject.

For some applications, the implantable sensor, the first control unit,the electrode device, and the second control unit are packaged in asingle integrated unit. For some applications, the second control unitis adapted to drive the electrode device responsively to the sensedparameter.

In an embodiment, the aspect of the operation of the first control unitincludes an aspect of timing of the operation of the first control unit,the aspect of the operation of the second control unit includes anaspect of timing of the operation of the second control unit, and the atleast one of the control units is adapted to coordinate the aspect ofthe timing of the operation of the first control unit with the aspect ofthe timing of the operation of the second control unit.

In an embodiment, the implantable sensor and the first control unittogether include an implantable cardioverter defibrillator (ICD). In anembodiment, the implantable sensor and the first control unit togetherinclude a pacemaker. In an embodiment, the implantable sensor and thefirst control unit together include a pulse generator.

In an embodiment, the second control unit is configured to reduce alikelihood that the current causes the first control unit to falselydetect arrhythmia of the subject.

In an embodiment, the at least one of the control units is configured toreduce a likelihood of an occurrence of a “tug-of-war” between the firstand second control units.

In an embodiment, the first control unit is programmed with a flagindicative of the presence of the second control unit, and the firstcontrol unit is adapted to withhold coordinating the aspect of theoperation responsively to a value of the flag that indicates that thesecond control unit is not present. Alternatively, in an embodiment, thesecond control unit is programmed with a flag indicative of the presenceof the first control unit, and the at least one of the control units isadapted to withhold coordinating the aspect of the operationresponsively to a value of the flag that indicates that the firstcontrol unit is not present.

In an embodiment, the first control unit is adapted to identify astimulus artifact of the current application by the electrode device asbeing a stimulus artifact of the current application by the electrodedevice.

For some applications, the second control unit is adapted to generate acommunication signal when driving the electrode device to apply thecurrent, and the first control unit is adapted to receive the signal,and, responsively thereto, to withhold applying the pulses.

In an embodiment, the implantable device is adapted to detect anoccurrence of arrhythmia only if the arrhythmia continues for a firstnumber of consecutive heart beats, and the control unit is adapted todrive the electrode device to apply the current for a maximum of asecond number of consecutive heart beats, the second number less thanthe first number.

For some applications, the second control unit is adapted to drive theelectrode device to apply the current intermittently during alternating“on” and “off” periods, each of the “on” periods having an “on” durationequal to between 1 and 10 seconds, and each of the “off” periods havingan “off” duration equal to at least 50% of the “on” duration. For someapplications, the second control unit is adapted to drive the electrodedevice to apply the current in respective bursts of pulses in each of aplurality of cardiac cycles of the subject.

In an embodiment, the first control unit is adapted to withholdattempting to detect a next heart beat during an extended blankingperiod following detection of a previous heart beat. For someapplications, the extended blanking period has a duration of between 20and 200 ms, and the first control unit is adapted to withhold attemptingto detect the next heart beat during the extended blanking period havingthe duration. For some applications, the second control unit is adaptedto drive the electrode device to apply the current only during theextended blanking period.

In an embodiment, the site includes the vagus nerve, and the electrodedevice is adapted to be coupled to the vagus nerve. For someapplications, the second control unit is adapted to configure thecurrent to include a stimulating current, which is capable of inducingaction potentials in a first set and a second set of nerve fibers of thevagus nerve, and an inhibiting current, which is capable of inhibitingthe induced action potentials traveling in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set. For some applications,the second control unit is adapted to configure the current to include astimulating current, which is capable of inducing action potentials inthe vagus nerve, and an inhibiting current, which is capable ofinhibiting action potentials induced by the stimulating current andtraveling in the vagus nerve in an afferent direction toward a brain ofthe subject.

In an embodiment, the first control unit is adapted to generate acommunication signal at each detection of a feature of a cardiac cycleof the subject, and the second control unit is adapted to receive thesignal, and to time an aspect of the application of the currentresponsively to the signal. For some applications, the feature includesan R-wave of an electrocardiogram (ECG) of subject, and the firstcontrol unit is adapted to generate the signal at each detection of theR-wave.

In an embodiment, the second control unit is adapted to, upon detectionof suspected arrhythmia, drive the electrode device to apply thecurrent, and to configure the current to reduce a ventricular rate. Forsome applications, the implantable sensor and the first control unittogether include an implantable cardioverter defibrillator (ICD), andthe ICD is adapted to apply defibrillation to the heart if the appliedcurrent does not sufficiently reduce the ventricular rate.

In an embodiment, the first control unit is adapted to detectventricular fibrillation (VF), to generate a communication signalresponsive to the detection, and to withhold generating the signal afterthe detection ceases; and the second control unit is adapted to receivethe signal, and, responsively thereto, to withhold driving the electrodedevice to apply the current until cessation of the signal. For someapplications, in the absence of detection of VF by the implantabledevice, the second control unit is adapted to continue driving theelectrode device to apply the current notwithstanding any detection ofventricular tachycardia by the first control unit. For someapplications, in the absence of detection of VF by the first controlunit, the second control unit is adapted to continue driving theelectrode device to apply the current notwithstanding any detection ofsupraventricular tachycardia by the first control unit.

In an embodiment, the second control unit is adapted to detectventricular fibrillation (VF), and, responsively thereto, to withholddriving the electrode device to apply the current until cessation of theVF. For some applications, in the absence of detection of VF by thesecond control unit, the second control unit is adapted to continuedriving the electrode device to apply the current notwithstanding anydetection of ventricular tachycardia by the second control unit. Forsome applications, in the absence of detection of VF by the secondcontrol unit, the second control unit is adapted to continue driving theelectrode device to apply the current notwithstanding any detection ofsupraventricular tachycardia by the second control unit.

In an embodiment, the first control unit is adapted to detectventricular tachycardia (VT), to generate a communication signalresponsive to the detection, and to withhold generating the signal afterthe detection ceases; and the second control unit is adapted to receivethe signal, and, responsively thereto, to withhold driving the electrodedevice to apply the current until cessation of the signal. For someapplications, in the absence of detection of VT by the first controlunit, the second control unit is adapted to continue driving theelectrode device to apply the current, notwithstanding any detection ofnon-ventricular-origin tachycardia by the first control unit. For someapplications, in the absence of detection of VT by the first controlunit, the second control unit is adapted to continue driving theelectrode device to apply the current, notwithstanding any detection ofsupraventricular tachycardia by the first control unit.

In an embodiment, the second control unit is adapted to detectventricular tachycardia (VT), and, responsively thereto, to withholddriving the electrode device to apply the current until cessation of theVT. For some applications, in the absence of detection of VT by thesecond control unit, the second control unit is adapted to continuedriving the electrode device to apply the current, notwithstanding anydetection of a non-ventricular-origin tachycardia by the second controlunit. For some applications, in the absence of detection of VT by thesecond control unit, the second control unit is adapted to continuedriving the electrode device to apply the current, notwithstanding anydetection of supraventricular tachycardia by the second control unit.

In an embodiment, the first control unit is adapted to detectventricular fibrillation (VF), to generate a communication signalresponsive to the detection, and to withhold generating the signal afterthe detection ceases; the first control unit is adapted to detectventricular tachycardia (VT), and generate the signal responsively tothe detection, and to withhold generating the signal after the detectionceases; and the second control unit is adapted to receive the signal,and, responsively thereto, to withhold driving the electrode device toapply the current until cessation of the signal. For some applications,in the absence of detection of VF by the first control unit, and in theabsence of detection of VT by the first control unit, the second controlunit is adapted to continue driving the electrode device to apply thecurrent notwithstanding any detection of a non-ventricular-origintachycardia by the first control unit. For some applications, in theabsence of detection of VF by the first control unit, and in the absenceof detection of VT by the first control unit, the second control unit isadapted to continue driving the electrode device to apply the currentnotwithstanding detection of supraventricular tachycardia by the firstcontrol unit.

In an embodiment, the second control unit is adapted to detectventricular fibrillation (VF), and, responsively thereto, to withholddriving the electrode device to apply the current until cessation of theVF; and the second control unit is adapted to detect ventriculartachycardia (VT), and, responsively thereto, to withhold driving theelectrode device to apply the current until cessation of the VT. Forsome applications, in the absence of detection of VF by the secondcontrol unit, and in the absence of detection of VT by the secondcontrol unit, the second control unit is adapted to continue driving theelectrode device to apply the current notwithstanding any detection of anon-ventricular-origin tachycardia by the second control unit. For someapplications, in the absence of detection of VF by the second controlunit, and in the absence of detection of VT by the second control unit,the second control unit is adapted to continue driving the electrodedevice to apply the current notwithstanding detection ofsupraventricular tachycardia by the second control unit.

In an embodiment, the first control unit is adapted to generate acommunication signal when applying pulses to the heart, and to withholdgenerating the signal when not applying the pulses; and the secondcontrol unit is adapted to receive the signal, and, responsivelythereto, to withhold driving the electrode device to apply the currentuntil a certain amount of time after cessation of the signal.

In an embodiment, the second control unit is adapted to drive theelectrode device to apply the current during at least one periodselected from the list consisting of: a refractory period of the heart,and a blanking period of the first control unit. For some applications,the second control unit is adapted to drive the electrode device toapply the current during at least a portion of a period beginning upondetection of a QRS complex and ending 100 milliseconds after thedetection of the QRS complex.

In an embodiment, the first control unit is adapted to apply the pulsesonly when the heart rate is within a first set of values, and the secondcontrol unit is adapted to drive the electrode device to apply thecurrent only when the heart rate is within a second set of values. Forsome applications, the first and second sets of values arenon-overlapping. For some applications, the first set of values includesvalues greater than 190 beats per minute and less than 60 beats perminute, and the second set of values includes values between 70 and 180beats per minute.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for classifying an arrhythmia including:

-   -   an implantable sensor adapted to sense an electrical parameter        of a heart of a subject;    -   an electrode device, adapted to be coupled to a site of the        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to:    -   detect an occurrence of arrhythmia responsively to the sensed        electrical parameter,    -   upon detecting the occurrence of the arrhythmia, drive the        electrode device to apply a current to the site that increases        parasympathetic tone of the subject,    -   determine whether the applied current affects a physiological        parameter selected from the list consisting of: heart rate and        heart rate variability, and    -   responsively to a determination that the applied current affects        the physiological parameter, determine that the arrhythmia is        not of ventricular origin.

For some applications, the control unit is adapted to determine that thearrhythmia is neither VT nor ventricular fibrillation (VF).

For some applications, the apparatus includes an implantablecardioverter defibrillator (ICD), of which the implantable sensor is acomponent.

For some applications, the physiological parameter includes the heartrate, and the control unit is adapted to determine whether the appliedcurrent affects the heart rate. For some applications, the control unitis adapted to configure the current to attempt to lower the heart rate.

For some applications, the physiological parameter includes the heartrate variability, and the control unit is adapted to determine whetherthe applied current affects the heart rate variability. For someapplications, the control unit is adapted to configure the current toattempt to lower the heart rate variability.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an implantable sensor, adapted to sense an electrical parameter        of a heart of a subject;    -   a first control unit, adapted to apply cardiac resynchronization        therapy (CRT) pulses to the heart responsively to the sensed        parameter;    -   an electrode device, adapted to be coupled to a site of the        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a second control unit, adapted to drive the electrode device to        apply to the site a current that increases parasympathetic tone        of the subject and increases an AV delay of the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus including:

-   -   an implantable cardioverter defibrillator (ICD), configured to        apply therapeutic pulses to a heart of a subject upon detection        of ventricular arrhythmia;    -   an electrode device, adapted to be coupled to a site of the        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject; and    -   a control unit, adapted to drive the electrode device to apply        to the site, upon the detection of the ventricular arrhythmia, a        current that increases parasympathetic tone of the subject.

For some applications, the control unit is adapted to configure thecurrent to reduce a heart rate of the subject. For some applications,the control unit is adapted to configure the current to prolong AV nodedelay. For some applications, the control unit is adapted to configurethe current to increase heart rate variability.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a sensing element, adapted to sense a physiological parameter of        the subject; and    -   a control unit, adapted to drive the electrode device to apply        to the site a current that increases parasympathetic tone of the        subject, and, responsively to the sensed physiological        parameter, to configure the current to treat bundle branch block        of the subject.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a sensing element, adapted to sense a physiological parameter of        a heart of the subject;    -   an implantable device adapted to apply pulses to the heart, the        pulses selected from the list consisting of: pacing pulses and        anti-arrhythmic energy; and    -   a control unit, adapted to:        -   detect a life-threatening arrhythmia (LTA) responsively to            the sensed physiological parameter,        -   responsively to the detection of the LTA, drive the            electrode device to apply to the site a current that            increases parasympathetic tone of the subject,        -   determine whether the LTA has been resolved,        -   responsively to a determination that the LTA has not been            resolved, determine whether to drive the implantable device            to apply the pulses to the heart,        -   responsively to an affirmative determination to drive the            implantable device, drive the implantable device to apply            the pulses to the heart, and        -   responsively to a determination not to drive the implantable            device, drive the electrode device to apply the current to            the site.

For some applications, the control unit is adapted to change a parameterof the current applied to the site, after the determination not to drivethe implantable device.

For some applications, the implantable device includes an implantablecardioverter defibrillator (ICD). For some applications, the implantabledevice includes a pacemaker.

For some applications, the parameter includes a feature of anelectrocardiogram (ECG) signal, and the sensing element is adapted tosense the feature.

For some applications, the control unit is adapted to determine to drivethe implantable device to apply the pulses only if the control unitdetermines that only driving the electrode device to apply the currentis unlikely to resolve the LTA.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus including:

-   -   an electrode device, adapted to be coupled to a site of a        subject selected from the list consisting of: a vagus nerve of        the subject, an epicardial fat pad of the subject, a pulmonary        vein of the subject, a carotid artery of the subject, a carotid        sinus of the subject, a coronary sinus of the subject, a vena        cava vein of the subject, a right ventricle of the subject, and        a jugular vein of the subject;    -   a sensing element, adapted to sense a physiological parameter of        a heart of the subject;    -   an implantable device adapted to apply pulses to the heart, the        pulses selected from the list consisting of: pacing pulses and        anti-arrhythmic energy; and    -   a control unit, adapted to:        -   drive the electrode device to apply to the site a current            that increases parasympathetic tone of the subject,        -   detect a life-threatening arrhythmia (LTA) responsively to            the sensed physiological parameter,        -   responsively to the detection of the LTA, modify at least            one current parameter of the applied current,        -   determine whether the LTA has been resolved,        -   responsively to a determination that the LTA has not been            resolved, determine whether to drive the implantable device            to apply the pulses to the heart,        -   responsively to an affirmative determination to drive the            implantable device, drive the implantable device to apply            the pulses to the heart, and        -   responsively to a determination not to drive the implantable            device, modify one or more current parameters of the applied            current.

For some applications, the implantable device includes an implantablecardioverter defibrillator (ICD). For some applications, the implantabledevice includes a pacemaker.

For some applications, the parameter includes a feature of anelectrocardiogram (ECG) signal, and the sensing element is adapted tosense the feature.

For some applications, the control unit is adapted to determine to drivethe implantable device to apply the pulses only if the control unitdetermines that only driving the electrode device to apply the currentis unlikely to resolve the LTA.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   sensing, from within a body of a subject, an electrical        parameter of a heart of the subject;    -   applying, from a first implantation site within the body, pulses        to the heart responsive to the parameter, the pulses selected        from the list consisting of: pacing pulses and anti-arrhythmic        energy;    -   applying, at a second implantation site within the body, a        current that increases parasympathetic tone of the subject and        affects a heart rate of the subject, the second implantation        site selected from the list consisting of: a vagus nerve of the        subject, an epicardial fat pad of the subject, a pulmonary vein        of the subject, a carotid artery of the subject, a carotid sinus        of the subject, a coronary sinus of the subject, a vena cava        vein of the subject, a right ventricle of the subject, and a        jugular vein of the subject; and    -   coordinating an aspect of applying the pulses with an aspect of        applying the current, without providing a controller that        regulates both the applying of the pulses and the applying of        the current.

For some applications, sensing the electrical parameter includesimplanting, in the subject, a device for sensing the electricalparameter, and applying the pulses includes applying the pulses from thedevice.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for classifying an arrhythmia including:

-   -   sensing an electrical parameter of a heart of a subject;    -   detecting an occurrence of arrhythmia responsively to the sensed        electrical parameter;    -   upon detecting the occurrence of the arrhythmia, applying to a        site of the subject a current that increases parasympathetic        tone of the subject, the site selected from the list consisting        of: a vagus nerve of the subject, an epicardial fat pad of the        subject, a pulmonary vein of the subject, a carotid artery of        the subject, a carotid sinus of the subject, a coronary sinus of        the subject, a vena cava vein of the subject, a right ventricle        of the subject, and a jugular vein of the subject;    -   determining whether the applied current affects a physiological        parameter selected from the list consisting of: heart rate and        heart rate variability; and    -   responsively to a determination that the applied current affects        the physiological parameter, determining that the arrhythmia is        not of ventricular origin.

For some applications, determining that the arrhythmia is notventricular tachycardia (VT) of ventricular origin includes determiningthat the arrhythmia is neither VT nor ventricular fibrillation (VF).

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   implanting in a subject an implantable cardioverter        defibrillator (ICD);    -   configuring the ICD to apply therapeutic pulses to a heart of        the subject upon detection of ventricular arrhythmia; and    -   upon the detection of the ventricular arrhythmia, applying to a        site of the subject a current that increases parasympathetic        tone of the subject, the site selected from the list consisting        of: a vagus nerve of the subject, an epicardial fat pad of the        subject, a pulmonary vein of the subject, a carotid artery of        the subject, a carotid sinus of the subject, a coronary sinus of        the subject, a vena cava vein of the subject, a right ventricle        of the subject, and a jugular vein of the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method including:

-   -   sensing a physiological parameter of a subject;    -   applying to a site of the subject a current that increases        parasympathetic tone of the subject, the site selected from the        list consisting of: a vagus nerve of the subject, an epicardial        fat pad of the subject, a pulmonary vein of the subject, a        carotid artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and a jugular vein of the        subject; and    -   responsively to the sensed physiological parameter, configuring        the current to treat bundle branch block of the subject.

There is also provided, in accordance with an embodiment of the presentinvention, a method for surgically implanting an electrode device in avicinity of a nerve, including:

-   -   placing the electrode device around the nerve;    -   introducing conductive solution into the electrode device such        that the solution is in contact with both the electrode device        and the nerve;    -   during implantation of the electrode device, measuring an        impedance between one or more electrodes of the electrode device        and an electrical contact point in electrical communication with        the electrode device; and    -   responsively to the impedance measurement, determining whether        the electrodes are positioned appropriately, and whether        sufficient conductive solution is in the electrode device.

For some applications, the conductive solution includes saline solution,and introducing the conductive solution includes introducing the salinesolution.

For some applications, the nerve includes a vagus nerve, and placing theelectrode device around the nerve includes placing the electrode devicearound the vagus nerve.

For some applications, the method includes, responsively to theimpedance measurement, determining whether the electrodes are correctlysized for the nerve. For some applications, determining whether theelectrodes are positioned appropriately includes determining whether theelectrodes are in good electrical contact with the nerve.

For some applications, determining whether the electrodes are positionedappropriately includes interpreting a value of the impedance measurementbetween 100 and 300 ohms as an indication that the electrodes are notpositioned appropriately. For some applications, determining whether theelectrodes are positioned appropriately includes interpreting a value ofthe impedance measurement between 300 and 1000 ohms as an indicationthat the electrodes are positioned appropriately. For some applications,determining whether sufficient conductive solution is in the electrodedevice includes interpreting a value of the impedance measurementgreater than 1000 ohms as an indication that insufficient conductivesolution is in the electrode device.

For some applications, the one or more electrodes of the electrodedevice include at least first and second electrodes, the electricalcontact point includes the first one of the electrodes, and measuringthe impedance includes measuring the impedance between the first andsecond electrodes.

For some applications, the electrical contact point is located outsideof the electrode device, and measuring the impedance includes measuringthe impedance between the one or more electrodes and the electricalcontact point located outside of the electrode device.

There is further provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   sensing, from within a body of a subject, a physiological        parameter of a heart of the subject;    -   detecting a life-threatening arrhythmia (LTA) responsively to        the sensed physiological parameter;    -   responsively to the detection of the LTA, applying to a site of        the subject a current that increases parasympathetic tone of the        subject, the site selected from the list consisting of: a vagus        nerve of the subject, an epicardial fat pad of the subject, a        pulmonary vein of the subject, a carotid artery of the subject,        a carotid sinus of the subject, a coronary sinus of the subject,        a vena cava vein of the subject, a right ventricle of the        subject, and a jugular vein of the subject;    -   determining whether the LTA has been resolved;    -   responsively to a determination that the LTA has not been        resolved, determining whether to apply, from within the body,        pulses to the heart selected from the list consisting of: pacing        pulses and anti-arrhythmic energy;    -   responsively to an affirmative determination to apply the        pulses, applying the pulses to the heart; and    -   responsively to a determination not to apply the pulses,        applying the current to the site.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including:

-   -   applying to a site of a subject a current that increases        parasympathetic tone of the subject, the site selected from the        list consisting of: a vagus nerve of the subject, an epicardial        fat pad of the subject, a pulmonary vein of the subject, a        carotid artery of the subject, a carotid sinus of the subject, a        coronary sinus of the subject, a vena cava vein of the subject,        a right ventricle of the subject, and a jugular vein of the        subject;    -   sensing, from within a body of the subject, a physiological        parameter of a heart of the subject;    -   detecting a life-threatening arrhythmia (LTA) responsively to        the sensed physiological parameter;    -   responsively to the detection of the LTA, modifying at least one        current parameter of the applied current;    -   determining whether the LTA has been resolved;    -   responsively to a determination that the LTA has not been        resolved, determining whether to apply, from within the body,        pulses to the heart selected from the list consisting of: pacing        pulses and anti-arrhythmic energy;    -   responsively to an affirmative determination to apply the        pulses, applying the pulses to the heart; and    -   responsively to a determination not to apply the pulses,        modifying one or more current parameters of the applied current.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram that schematically illustrates a vagalstimulation system applied to a vagus nerve of a subject, in accordancewith an embodiment of the present invention;

FIG. 2A is a simplified cross-sectional illustration of a multipolarelectrode device applied to a vagus nerve, in accordance with anembodiment of the present invention;

FIG. 2B is a simplified cross-sectional illustration of agenerally-cylindrical electrode device applied to a vagus nerve, inaccordance with an embodiment of the present invention;

FIG. 2C is a simplified perspective illustration of the electrode deviceof FIG. 2A, in accordance with an embodiment of the present invention;

FIG. 3 is a conceptual illustration of the application of current to avagus nerve, in accordance with an embodiment of the present invention;

FIG. 4 is a simplified illustration of an electrocardiogram (ECG)recording and of example timelines showing the timing of the applicationof a series of stimulation pulses, in accordance with an embodiment ofthe present invention;

FIGS. 5 and 6 are graphs illustrating experimental results measured inaccordance with an embodiment of the present invention; and

FIGS. 7 and 8 are flow charts that schematically illustrate respectivemethods for treating life-threatening arrhythmia (LTA), in accordancewith respective embodiments of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

FIG. 1 is a block diagram that schematically illustrates a vagalstimulation system 18 comprising a multipolar electrode device 26, inaccordance with an embodiment of the present invention. Electrode device26 is applied to a portion of a vagus nerve 36 (a left vagus nerve 37and/or a right vagus nerve 39), which innervates a heart 30 of a subject31. Alternatively, electrode device 26 is applied to an epicardial fatpad, a pulmonary vein, a carotid artery, a carotid sinus, a coronarysinus, a vena cava vein, a right ventricle, or a jugular vein(configurations not shown). Typically, system 18 is utilized fortreating a heart condition such as heart failure and/or cardiacarrhythmia. Vagal stimulation system 18 further comprises an implantableor external control unit 20, which typically communicates with electrodedevice 26 over a set of leads 42. Typically, control unit 20 driveselectrode device 26 to (i) apply signals to induce the propagation ofefferent nerve impulses towards heart 30, and (ii) suppressartificially-induced afferent nerve impulses towards a brain 34 of thesubject, in order to minimize unintended side effects of the signalapplication. The efferent nerve pulses in vagus nerve 36 are typicallyinduced by electrode device 26 in order to regulate the heart rate ofthe subject.

For some applications, control unit 20 is adapted to receive feedbackfrom one or more of the electrodes in electrode device 26, and toregulate the signals applied to the electrode device responsive thereto.

Control unit 20 is typically adapted to receive and analyze one or moresensed physiological parameters or other parameters of the subject, suchas heart rate, electrocardiogram (ECG), blood pressure, indicators ofdecreased cardiac contractility, cardiac output, norepinephrineconcentration, left ventricular end diastolic pressure (LVEDP), ormotion of the subject. In order to receive these sensed parameters,control unit 20 may comprise, for example, an ECG monitor 24, connectedto a site on the subject's body such as heart 30, for example using oneor more subcutaneous sensors or ventricular and/or atrial intracardiacsensors. The control unit may also comprise an accelerometer 22 fordetecting motion of the subject. Alternatively, ECG monitor 24 and/oraccelerometer 22 comprise separate implanted devices placed external tocontrol unit 20, and, optionally, external to the subject's body.Alternatively or additionally, control unit 20 receives signals from oneor more physiological sensors 28, such as blood pressure sensors.Sensors 28 are typically implanted in the subject, for example in a leftventricle 32 of heart 30. For example, sensors 28 may comprise apressure gauge for measuring LVEDP, which gauge may be adapted to beplaced in left ventricle 32, a left atrium 33 of heart 30, or in apulmonary artery.

FIG. 2A is a simplified cross-sectional illustration of agenerally-cylindrical electrode device 40 applied to vagus nerve 36, inaccordance with an embodiment of the present invention. For someapplications, electrode device 26 (FIG. 1) comprises electrode device40. Alternatively, electrode device 26 comprises an electrode deviceknown in the art of nerve stimulation, such as those described in someof the references incorporated herein by reference. Electrode device 40comprises a central cathode 46 for applying a negative current(“cathodic current”) in order to stimulate vagus nerve 36, as describedbelow. Electrode device 40 additionally comprises a set of one or moreanodes 44 (44 a, 44 b, herein: “efferent anode set 44”), placed betweencathode 46 and the edge of electrode device 40 closer to heart 30 (the“efferent edge”). Efferent anode set 44 applies a positive current(“efferent anodal current”) to vagus nerve 36, for blocking actionpotential conduction in vagus nerve 36 induced by the cathodic current,as described below. Typically, electrode device 40 comprises anadditional set of one or more anodes 45 (45 a, 45 b, herein: “afferentanode set 45”), placed between cathode 46 and the edge of electrodedevice 40 closer to brain 34. Afferent anode set 45 applies a positivecurrent (“afferent anodal current”) to vagus nerve 36, in order to blockpropagation of action potentials in the direction of the brain duringapplication of the cathodic current.

For some applications, the one or more anodes of efferent anode set 44are directly electrically coupled to the one or more anodes of afferentanode set 45, such as by a common wire or shorted wires providingcurrent to both anode sets substantially without any intermediaryelements. Typically, coatings on the anodes, shapes of the anodes,positions of the anodes, sizes of the anodes and/or distances of thevarious anodes from the nerve are regulated so as to produce desiredratios of currents and/or desired activation functions delivered throughor caused by the various anodes. For example, by varying one or more ofthese characteristics, the relative impedance between the respectiveanodes and central cathode 46 is regulated, whereupon more anodalcurrent is driven through the one or more anodes having lower relativeimpedance. In these applications, central cathode 46 is typically placedcloser to one of the anode sets than to the other, for example, so as toinduce asymmetric stimulation (i.e., not necessarily unidirectional inall fibers) between the two sides of the electrode device. The closeranode set typically induces a stronger blockade of the cathodicstimulation.

Reference is now made to FIG. 2B, which is a simplified cross-sectionalillustration of a generally-cylindrical electrode device 240 applied tovagus nerve 36, in accordance with an embodiment of the presentinvention. Electrode device 240 comprises exactly one efferent anode 244and exactly one afferent anode 245, which are electrically coupled toeach other, such as by a common wire 250 or shorted wires providingcurrent to both anodes 244 and 245, substantially without anyintermediary elements. The cathodic current is applied by a cathode 246with an amplitude sufficient to induce action potentials in large- andmedium-diameter fibers (e.g., A- and B-fibers), but insufficient toinduce action potentials in small-diameter fibers (e.g., C-fibers).

Reference is again made to FIG. 2A. Cathodes 46 and anode sets 44 and 45(collectively, “electrodes”) are typically mounted in anelectrically-insulating cuff 48 and separated from one another byinsulating elements such as protrusions 49 of the cuff. Typically, thewidth of the electrodes is between about 0.5 and about 2 millimeters, oris equal to approximately one-half the radius of the vagus nerve. Theelectrodes are typically recessed so as not to come in direct contactwith vagus nerve 36. For some applications, such recessing enables theelectrodes to achieve generally uniform field distributions of thegenerated currents and/or generally uniform values of the activationfunction defined by the electric potential field in the vicinity ofvagus nerve 24. Alternatively or additionally, protrusions 49 allowvagus nerve 24 to swell into the canals defined by the protrusions,while still holding the vagus nerve centered within cuff 48 andmaintaining a rigid electrode geometry. For some applications, cuff 48comprises additional recesses separated by protrusions, which recessesdo not contain active electrodes. Such additional recesses accommodateswelling of vagus nerve 24 without increasing the contact area betweenthe vagus nerve and the electrodes.

For some applications, the distance between the electrodes and the axisof the vagus nerve is between about 1 and about 4 millimeters, and isgreater than the closest distance from the ends of the protrusions tothe axis of the vagus nerve. Typically, protrusions 49 are relativelyshort (as shown). For some applications, the distance between the endsof protrusions 49 and the center of the vagus nerve is between about 1and 3 millimeters. (Generally, the diameter of the vagus nerve isbetween about 2 and 3 millimeters.) Alternatively, for someapplications, protrusions 49 are longer and/or the electrodes are placedcloser to the vagus nerve in order to reduce the energy consumption ofelectrode device 40.

In an embodiment of the present invention, efferent anode set 44comprises a plurality of anodes 44, typically two anodes 44 a and 44 b,spaced approximately 0.5 to 2.0 millimeters apart. Application of theefferent anodal current in appropriate ratios from a plurality of anodesgenerally minimizes the “virtual cathode effect,” whereby application oftoo large an anodal current stimulates rather than blocks fibers. In anembodiment, anode 44 a applies a current with an amplitude equal toabout 0.5 to about 5 milliamps (typically one-third of the amplitude ofthe current applied by anode 44 b). When such techniques are not used,the virtual cathode effect generally hinders blocking ofsmaller-diameter fibers, as described below, because a relatively largeanodal current is generally necessary to block such fibers.

Anode 44 a is typically positioned in cuff 48 to apply current at thelocation on vagus nerve 36 where the virtual cathode effect is maximallygenerated by anode 44 b. For applications in which the blocking currentthrough anode 44 b is expected to vary substantially, efferent anode set44 typically comprises a plurality of virtual-cathode-inhibiting anodes44 a, one or more of which is activated at any time based on theexpected magnitude and location of the virtual cathode effect.

Likewise, afferent anode set 45 typically comprises a plurality ofanodes 45, typically two anodes 45 a and 45 b, in order to minimize thevirtual cathode effect in the direction of the brain. In certainelectrode configurations, cathode 46 comprises a plurality of cathodesin order to minimize the “virtual anode effect,” which is analogous tothe virtual cathode effect.

FIG. 2C is a simplified perspective illustration of electrode device 40(FIG. 2A), in accordance with an embodiment of the present invention.When applied to vagus nerve 36, electrode device 40 typicallyencompasses the nerve. As described, control unit 20 typically driveselectrode device 40 to (i) apply signals to vagus nerve 36 in order toinduce the propagation of efferent action potentials towards heart 30,and (ii) suppress artificially-induced afferent action potentialstowards brain 34. The electrodes typically comprise ring electrodesadapted to apply a generally uniform current around the circumference ofthe nerve, as best shown in FIG. 2C.

Alternatively, ordinary, non-cuff electrodes are used, such as when theelectrodes are placed on the epicardial fat pads instead of on the vagusnerve.

In an embodiment of the present invention, a method for surgicallyimplanting electrode device 26 comprises: (a) placing the electrodedevice around vagus nerve 36, (b) during the implantation procedure,introducing conductive solution (e.g., saline solution) into theelectrode device such that the solution is in contact with both theelectrodes and the nerve, and (c) measuring an inter-electrode impedanceduring the implantation procedure. Such an impedance measurement enablesthe surgeon to determine during the procedure (a) whether the electrodesare positioned appropriately, (b) whether sufficient conductive solutionhas been introduced into and remained in electrode device 26, (c)whether the electrodes are the correct size for the nerve, and (d)whether the electrodes are in good contact with the nerve. Expectedvalues for the impedance measurement, and their typical interpretations,include:

-   -   a low value, such as between about 100 and about 300 ohms, which        typically occurs if the electrodes are in poor contact with the        nerve, such as because the diameter of the electrode is larger        than that of the nerve. When there is such poor contact, the        electrodes are short-circuited by the conductive solution,        resulting in the low impedance;    -   a high value, such as greater than about 1000 ohms, which        typically occurs if electrode device 26 is not filled properly        with conductive solution, which causes a disconnect between the        electrodes and the nerve; or    -   a medium value, such as between about 300 and about 1000 ohms,        which indicates that the electrodes are in good contact with the        nerve, so that most of the current travels through the nerve.

If the impedance differs from an expected value, the surgeon correctsthe placement by, for example, repositioning the electrode device,removing the electrode device and implanting another electrode devicehaving a different size, and/or introducing additional conductivesolution into the electrode device. The techniques of this embodimentare also applicable to implanting electrode devices on a body tissueother than the vagus nerve.

FIG. 3 is a conceptual illustration of the application of current tovagus nerve 36 in order to achieve smaller-to-larger diameter fiberrecruitment, in accordance with an embodiment of the present invention.When inducing efferent action potentials towards heart 30, control unit20 drives electrode device 40 to selectively recruit nerve fibersbeginning with smaller-diameter fibers and to progressively recruitlarger-diameter fibers as the desired stimulation level increases. Thissmaller-to-larger diameter recruitment order mimics the body's naturalorder of recruitment.

Typically, in order to achieve this recruitment order, the control unitstimulates myelinated fibers essentially of all diameters using cathodiccurrent from cathode 46, while simultaneously inhibiting fibers in alarger-to-smaller diameter order using efferent anodal current fromefferent anode set 44. For example, FIG. 3 illustrates the recruitmentof a single, smallest nerve fiber 56, without the recruitment of anylarger fibers 50, 52 and 54. The depolarizations generated by cathode 46stimulate all of the nerve fibers shown, producing action potentials inboth directions along all the nerve fibers. Efferent anode set 44generates a hyperpolarization effect sufficiently strong to block onlythe three largest nerve fibers 50, 52 and 54, but not fiber 56. Thisblocking order of larger-to-smaller diameter fibers is achieved becauselarger nerve fibers are inhibited by weaker anodal currents than aresmaller nerve fibers. Stronger anodal currents inhibit progressivelysmaller nerve fibers. When the action potentials induced by cathode 46in larger fibers 50, 52 and 54 reach the hyperpolarized region in thelarger fibers adjacent to efferent anode set 44, these action potentialsare blocked. On the other hand, the action potentials induced by cathode46 in smallest fiber 56 are not blocked, and continue travelingunimpeded toward heart 30. Anode pole 44 a is shown generating lesscurrent than anode pole 44 b in order to minimize the virtual cathodeeffect in the direction of the heart, as described above.

When desired, in order to increase the parasympathetic stimulationdelivered to the heart, the number of fibers not blocked isprogressively increased by decreasing the amplitude of the currentapplied by efferent anode set 44. The action potentials induced bycathode 46 in the fibers now not blocked travel unimpeded towards theheart. As a result, the parasympathetic stimulation delivered to theheart is progressively increased in a smaller-to-larger diameter fiberorder, mimicking the body's natural method of increasing stimulation.Alternatively or additionally, in order to increase the number of fibersstimulated, while simultaneously decreasing the average diameter offibers stimulated, the amplitudes of the currents applied by cathode 46and efferent anode set 44 are both increased (thereby increasing boththe number of fibers stimulated and blocked). In addition, for any givennumber of fibers stimulated (and not blocked), the amount of stimulationdelivered to the heart can be increased by increasing the PPT,frequency, and/or pulse width of the current applied to vagus nerve 36.

In order to suppress artificially-induced afferent action potentialsfrom traveling towards the brain in response to the cathodicstimulation, control unit 20 typically drives electrode device 40 toinhibit fibers 50, 52, 54 and 56 using afferent anodal current fromafferent anode set 45. When the afferent-directed action potentialsinduced by cathode 46 in all of the fibers reach the hyperpolarizedregion in all of the fibers adjacent to afferent anode set 45, theaction potentials are blocked. Blocking these afferent action potentialsgenerally minimizes any unintended side effects, such as undesired orcounterproductive feedback to the brain, that might be caused by theseaction potentials. Anode 45 b is shown generating less current thananode 45 a in order to minimize the virtual cathode effect in thedirection of the brain, as described above.

In an embodiment of the present invention, the amplitude of the cathodiccurrent applied in the vicinity of the vagus nerve is between about 2milliamps and about 10 milliamps. Such a current is typically used inembodiments that employ techniques for achieving generally uniformstimulation of the vagus nerve, i.e., stimulation in which thestimulation applied to fibers on or near the surface of the vagus nerveis generally no more than about 400% greater than stimulation applied tofibers situated more deeply in the nerve. This corresponds tostimulation in which the value of the activation function at fibers onor near the surface of the vagus nerve is generally no more than aboutfour times greater than the value of the activation function at fiberssituated more deeply in the nerve. For example, as described hereinabovewith reference to FIG. 2A, the electrodes may be recessed so as not tocome in direct contact with vagus nerve 24, in order to achievegenerally uniform values of the activation function. Typically, but notnecessarily, embodiments using approximately 5 mA of cathodic currenthave the various electrodes disposed approximately 0.5 to 2.5 mm fromthe axis of the vagus nerve. Alternatively, larger cathodic currents(e.g., 10-30 mA) are used in combination with electrode distances fromthe axis of the vagus nerve of greater than 2.5 mm (e.g., 2.5-4.0 mm),so as to achieve an even greater level of uniformity of stimulation offibers in the vagus nerve.

In an embodiment of the present invention, the cathodic current isapplied by cathode 46 with an amplitude sufficient to induce actionpotentials in large- and medium-diameter fibers 50, 52, and 54 (e.g., A-and B-fibers), but insufficient to induce action potentials insmall-diameter fibers 56 (e.g., C-fibers). Simultaneously, an anodalcurrent is applied by anode 44 b in order to inhibit action potentialsinduced by the cathodic current in the large-diameter fibers (e.g.,A-fibers). This combination of cathodic and anodal current generallyresults in the stimulation of medium-diameter fibers (e.g., B-fibers)only. At the same time, a portion of the afferent action potentialsinduced by the cathodic current are blocked by anode 45 a, as describedabove. Alternatively, the afferent anodal current is configured to notfully block afferent action potentials, or is simply not applied. Inthese cases, artificial afferent action potentials are neverthelessgenerally not generated in C-fibers, because the applied cathodiccurrent is not strong enough to generate action potentials in thesefibers.

These techniques for efferent stimulation of only B-fibers are typicallyused in combination with techniques described hereinabove for achievinggenerally uniform stimulation of the vagus nerve. Such generally uniformstimulation enables the use of a cathodic current sufficiently weak toavoid stimulation of C-fibers near the surface of the nerve, while stillsufficiently strong to stimulate B-fibers, including B-fibers situatedmore deeply in the nerve, i.e., near the center of the nerve. For someapplications, when employing such techniques for achieving generallyuniform stimulation of the vagus nerve, the amplitude of the cathodiccurrent applied by cathode 46 may be between about 3 and about 10milliamps, and the amplitude of the anodal current applied by anode 44 bmay be between about 1 and about 7 milliamps. (Current applied at adifferent site and/or a different time is used to achieve a net currentinjection of zero.)

In an embodiment of the present invention, stimulation of the vagusnerve is applied responsive to one or more sensed parameters. Controlunit 20 is typically configured to commence or halt stimulation, or tovary the amount and/or timing of stimulation in order to achieve adesired target heart rate, typically based on configuration values andon parameters including one or more of the following:

-   -   Heart rate—the control unit can be configured to drive electrode        device 26 to stimulate the vagus nerve only when the heart rate        exceeds a certain value.    -   ECG readings—the control unit can be configured to drive        electrode device 26 to stimulate the vagus nerve based on        certain ECG readings, such as readings indicative of designated        forms of arrhythmia. Additionally, ECG readings are typically        used for achieving a desire heart rate, as described below with        reference to FIG. 4.    -   Blood pressure—the control unit can be configured to regulate        the current applied by electrode device 26 to the vagus nerve        when blood pressure exceeds a certain threshold or falls below a        certain threshold.    -   Indicators of decreased cardiac contractility—these indicators        include left ventricular pressure (LVP). When LVP and/or        d(LVP)/dt exceeds a certain threshold or falls below a certain        threshold, control unit 20 can drive electrode device 26 to        regulate the current applied by electrode device 26 to the vagus        nerve.    -   Motion of the subject—the control unit can be configured to        interpret motion of the subject as an indicator of increased        exertion by the subject, and appropriately reduce        parasympathetic stimulation of the heart in order to allow the        heart to naturally increase its rate.    -   Heart rate variability—the control unit can be configured to        drive electrode device 26 to stimulate the vagus nerve based on        heart rate variability, which is typically calculated based on        certain ECG readings.    -   Norepinephrine concentration—the control unit can be configured        to drive electrode device 26 to stimulate the vagus nerve based        on norepinephrine concentration.    -   Cardiac output—the control unit can be configured to drive        electrode device 26 to stimulate the vagus nerve based on        cardiac output, which is typically determined using impedance        cardiography.    -   Baroreflex sensitivity—the control unit can be configured to        drive electrode device 26 to stimulate the vagus nerve based on        baroreflex sensitivity.    -   LVEDP—the control unit can be configured to drive electrode        device 26 to stimulate the vagus nerve based on LVEDP, which is        typically determined using a pressure gauge, as described        hereinabove with reference to FIG. 1.

The parameters and behaviors included in this list are for illustrativepurposes only, and other possible parameters and/or behaviors willreadily present themselves to those skilled in the art, having read thedisclosure of the present patent application.

In an embodiment of the present invention, control unit 20 is configuredto drive electrode device 26 to stimulate the vagus nerve so as toreduce the heart rate of the subject towards a target heart rate. Thetarget heart rate is typically (a) programmable or configurable, (b)determined responsive to one or more sensed physiological values, suchas those described hereinabove (e.g., motion, blood pressure, etc.),and/or (c) determined responsive to a time of day or circadian cycle ofthe subject. Parameters of stimulation are varied in real time in orderto vary the heart-rate-lowering effects of the stimulation. For example,such parameters may include the amplitude of the applied current.Alternatively or additionally, in an embodiment of the presentinvention, the stimulation is applied in bursts (i.e., series ofpulses), which are synchronized or are not synchronized with the cardiaccycle of the subject, such as described hereinbelow with reference toFIG. 4. Parameters of such bursts typically include, but are not limitedto:

-   -   Timing of the stimulation within the cardiac cycle. Delivery of        each of the bursts typically begins after a fixed or variable        delay following an ECG feature, such as each R- or P-wave. For        some applications, the delay is between about 20 ms and about        700 ms after the R-wave (e.g., about 100 ms after the R-wave),        or between about 100 and about 500 ms after the P-wave.    -   Pulse duration (width). Longer pulse durations typically result        in a greater heart-rate-lowering effect. For some applications,        the pulse duration is between about 0.1 and about 4 ms, such as        between about 100 microseconds and about 2.5 ms, e.g., about 1        ms.    -   Pulse repetition interval within each burst. Maintaining a pulse        repetition interval (the time from the initiation of a pulse to        the initiation of the following pulse within the same burst)        greater than about 3 ms generally results in maximal stimulation        effectiveness for multiple pulses within a burst. For some        applications, the pulse repetition interval is between about 1        and about 20 ms, such as between about 3 and about 10 ms, e.g.,        about 6 ms.    -   Pulses per trigger (PPT). A greater PPT (the number of pulses in        each burst after a trigger such as an R-wave) typically results        in a greater heart-rate-lowering effect. For some applications,        PPT is between about 0 and about 20 pulses, such as between        about 1 and about 10 pulses, e.g., 3 pulses. For some        applications, PPT is varied while pulse repetition interval is        kept constant.    -   Amplitude. A greater amplitude of the signal applied typically        results in a greater heart-rate-lowering effect. The amplitude        is typically less than about 20 milliamps, e.g., between about        0.1 and about 9 milliamps, e.g., about 2.5 milliamps. For some        applications, the amplitude is between about 2 and about 6        milliamps.    -   Duty cycle (number of bursts per heart beat). Application of        stimulation every heartbeat (i.e., with a duty cycle of 1)        typically results in a greater heart-rate-lowering effect. For        less heart rate reduction, stimulation is applied less        frequently than every heartbeat (e.g., duty cycle=60%-90%), or        only once every several heartbeats (e.g., duty cycle=5%-40%).    -   Choice of vagus nerve. Stimulation of the right vagus nerve        typically results in greater heart rate reduction than        stimulation of the left vagus nerve.    -   “On”/“off” ratio and timing. For some applications, the device        operates intermittently, alternating between “on” and “off”        states, the length of each state typically being between 0 and        about 1 day, such as between 0 and about 300 seconds (with a        O-length “off” state equivalent to always “on”). No stimulation        is applied during the “of P” state. Greater heart rate reduction        is typically achieved if the device is “on” a greater portion of        the time.

For some applications, values of one or more of the parameters aredetermined in real time, using feedback, i.e., responsive to one or moreinputs, such as sensed physiological values. For example, theintermittency (“on”/“off”) parameter may be determined in real timeusing such feedback. The inputs used for such feedback typically includeone or more of the following: (a) motion or activity of the subject(e.g., detected using an accelerometer), (b) the average heart rate ofthe subject, (c) the average heart rate of the subject when the deviceis in “off” mode, (d) the average heart rate of the subject when thedevice is in “on” mode, and/or (e) the time of day. The average heartrate is typically calculated over a period of at least about 10 seconds.For some applications, the average heart rate during an “on” or “off”period is calculated over the entire “on” or “off” period. For example,the device may operate in continuous “on” mode when the subject isexercising and therefore has a high heart rate, and the device mayalternate between “on” and “off” when the subject is at rest. As aresult, the heart-rate-lowering effect is concentrated during periods ofhigh heart rate, and the nerve is allowed to rest when the heart rate isgenerally naturally lower. For some applications, the device determinesthe ratio of “on” to “off” durations, the duration of the “on” periods,and/or the durations of the “off” periods using feedback. Optionally,the device determines the “on”/“off” parameter in real time using theintegral feedback techniques described hereinbelow, and/or otherfeedback techniques described hereinbelow, mutatis mutandis.

For some applications, heart rate regulation is achieved by setting twoor more parameters in combination. For example, if it is desired toapply 5.2 pulses of stimulation, the control unit may apply 5 pulses of1 ms duration each, followed by a single pulse of 0.2 ms duration. Forother applications, the control unit switches between two values of PPT,so that the desired PPT is achieved by averaging the applied PPTs. Forexample, a sequence of PPTs may be 5, 5, 5, 5, 6, 5, 5, 5, 5, 6, . . . ,in order to achieve an effective PPT of 5.2.

In an embodiment of the present invention, control unit 20 is configuredto apply vagal stimulation using feedback, as described hereinabove,wherein a parameter of the feedback is a target heart rate that is afunction of an average heart rate of the subject. For some applications,the target heart rate is set equal or approximately equal to the averageheart rate of the subject. Alternatively, the target heart rate is setat a rate greater than the average heart rate of the subject, such as anumber of beats per minute (BPM) greater than the average heart rate, ora percentage greater than the average heart rate, e.g., about 1% toabout 50% greater. Further alternatively, the target heart rate is setat a rate less than the average heart rate of the subject, such as anumber of BPM less than the average heart rate, or a percentage lessthan the average heart rate, e.g., about 1% to about 20% less. For someapplications, the target heart rate is set responsively to the dutycycle and the heart rate response of the subject. In an embodiment,control unit 20 determines the target heart rate in real time,periodically or substantially continuously, by sensing the heart rate ofthe subject and calculating the average heart rate of the subject. Theaverage heart rate is typically calculated substantially continuously,or periodically. Typically, standard techniques are used for calculatingthe average, such as moving averages or IIR filters. The number of beatsthat are averaged typically varies between several beats to all beatsduring the past week.

In an embodiment of the present invention, control unit 20 is configuredto apply the bursts using short “on” periods and, optionally, short“off” periods. Each of the short “on” periods typically has a durationof less than about 10 seconds, e.g., less than about 5 seconds. Whenshort “off” periods are used, each of the “off” periods typically has aduration of between about 5 and about 10 seconds. For example, the “on”periods may have a duration of about 3 seconds, and the “off” periodsmay have a duration of about 6 seconds. (Stimulation having theconfiguration described in this paragraph is referred to hereinbelow as“fast intermittent stimulation.”) The use of such short periodsgenerally allows stimulation of any given strength (e.g., as measured byamplitude of the signal, or by PPT of the signal) to be applied aseffectively as when using longer “on”/“off” periods, but with fewerpotential side effects. In addition, the use of such short “on” periodsgenerally allows side-effect-free application of stimulation at astrength that might increase the risk of side effects if applied forlonger “on” periods. It is believed by the inventors that the use ofsuch short periods generally reduces side effects by preventing build-upof sympathetic tone. In general, the parasympathetic reaction to vagalstimulation occurs more quickly than the sympathetic reaction to vagalstimulation. The short “on” periods are sufficiently long to stimulate adesired meaningful parasympathetic reaction, but not sufficiently longto stimulate an undesired, potentially side-effect-causing sympatheticreaction.

In an experiment performed in accordance with a preferred embodiment ofthe present invention, vagal stimulation was applied to a dog using twosets of stimulation parameters, and side effects were monitored. Thefirst set of stimulation parameters included continuous stimulation(i.e., stimulation every heart beat, without “on” and “off” periods), anamplitude of 6 milliamps, and a PPT of 2. Stimulation using this firstset of parameters induced cough in the dog. The second set ofstimulation parameters included “on” periods of 3 seconds and “off”periods of 6 seconds, an amplitude of 6 milliamps, and a PPT of 6.Stimulation with this second set of parameters did not induce cough inthe dog. Both sets of parameters delivered the same amount of totalstimulation, as expressed by current*pulses over any time periodincluding an equal number of “on” and “off” periods.

For some applications, a desired number of pulses per time period or perheart beat is delivered more effectively and/or with a reduced risk ofside effects, by using short “on” periods. For example, assume that itis desired to apply one pulse per trigger. Without the use of short “on”periods, one pulse per trigger could be achieved by applying one PPTconstantly. Using short “on” periods, one pulse per trigger couldinstead be achieved by applying 3 PPT for 3 heart beats (the “on”period), followed by an “off” period of 6 heart beats withoutstimulation. In both cases, in any given 9-heart-beat period, the samenumber of pulses (9) are applied. However, the use of short “on” periodsgenerally increases the effectiveness and reduces the potential sideeffects of the stimulations.

In an embodiment of the present invention, control unit 20 is configuredto apply vagal stimulation in alternating short “high” stimulation andshort “low” stimulation periods. Stimulation is applied with a greaterstrength during the “high” periods than during the “low” periods. “Low”strength, as used herein, including the claims, is to be understood asnot including zero strength, i.e., as excluding the non-application ofstimulation. Each of the short “high” periods typically has a durationof less than about 30 seconds (e.g., less than about 5 seconds), andeach of the short “low” periods typically has a duration of less thanabout 30 seconds (e.g., less than about 5 seconds). For someapplications, the “high” stimulation periods have a greater PPT than the“low” stimulation periods. Alternatively or additionally, the “high”stimulation periods have a greater amplitude than the “low” stimulationperiods. Further alternatively or additionally, control unit 20 adjustsone or more of the other parameters described herein in order to applythe “high” stimulation periods with a greater strength than the “low”stimulation periods.

In an embodiment of the present invention, control unit 20 is configuredto apply vagal stimulation intermittently using “on”/“off” periods, thedurations of which are expressed in heart beats, rather than in units oftime. In other words, the control unit alternatingly applies thestimulation for a first number of heart beats, and withholds applyingthe stimulation for a second number of heart beats. For example, thecontrol unit may alternatingly apply the stimulation for between about 1and about 30 heart beats, and withhold applying the stimulation forbetween about 5 and about 300 heart beats. Expressing the duration ofthe “on”/“off” periods in heart beats results in a constant duty cycle(expressed as “on”/(“on”+“off”)), while expressing the duration in unitsof time results in a variable duty cycle. In addition, expressing theduration of the “on”/“off” periods in heart beats results in theduration of the “on” and “off” periods varying based on the heart rate(at higher heart rates, the “on” and “off” periods are shorter).Furthermore, expressing the duration of the “on”/“off” periods in heartbeats tends to synchronize the stimulation with breathing, which isusually more rapid when the heart rate increases, such as duringexercise.

For one particular application, the control unit alternatingly appliesthe stimulation for exactly one heart beat, and withholds applying thestimulation for exactly one heart beat, i.e., the control unit appliesthe stimulation every other heart beat. Expressing the duration of“on”/“off” periods in heart beats typically allows precise control ofthe amount of stimulation applied and the physiological parameter thatis being modified, e.g., heart rate.

In an embodiment of the present invention, control unit 20 uses aslow-reacting heart rate regulation algorithm to modifyheart-rate-controlling parameters of the stimulation, i.e., thealgorithm varies stimulation parameters slowly in reaction to changes inheart rate. For example, in response to a sudden increase in heart rate,e.g., an increase from a target heart rate of 60 beats per minute (BPM)to 100 BPM over a period of only a few seconds, the algorithm slowlyincreases the stimulation level over a period of minutes. If the heartrate naturally returns to the target rate over this period, thestimulation levels generally do not change substantially beforereturning to baseline levels.

For example, the heart of a subject is regulated while the subject isinactive, such as while sitting. When the subject suddenly increases hisactivity level, such as by standing up or climbing stairs, the subject'sheart rate increases suddenly. In response, the control unit adjusts thestimulation parameters slowly to reduce the subject's heart rate. Such agradual modification of stimulation parameters allows the subject toengage in relatively stressful activities for a short period of timebefore his heart rate is substantially regulated, generally resulting inan improved quality of life.

In an embodiment of the present invention, control unit 20 is configuredto apply vagal stimulation intermittently using “on”/“off” periods, theduration of one of which type of periods is expressed in heart beats,and of the other is expressed in units of time. For example, theduration of the “on” periods may be expressed in heart beats (e.g., 2heart beats), and the duration of the “off” periods may be expressed inseconds (e.g., 2 seconds). In other words, in this example, the controlunit alternatingly applies the stimulation for a number of heart beats,and withholds applying the stimulation for a number of seconds. Forexample, the control unit may alternatingly apply the stimulation forbetween about 1 and about 100 heart beats, and withhold applying thestimulation for between about 1 and about 100 seconds. Expressing theduration of the “on”/“off” periods in this manner results in anautomatic reduction of the duty cycle as the heart rate increases,because, at higher heart rates, more heart beats occur during the “off”periods. As a result, stimulation is automatically reduced at higherrates, which may allow for increased activity and improved quality oflife.

In an embodiment of the present invention, control unit 20 is adapted todetect bradycardia (i.e., that an average detected R-R interval exceedsa preset bradycardia limit), and to terminate heart rate regulationsubstantially immediately upon such detection, such as by ceasing vagalstimulation. Alternatively or additionally, the control unit uses analgorithm that reacts quickly to regulate heart rate when the heart ratecrosses limits that are predefined (e.g., a low limit of 40 beats perminute (BPM) and a high limit of 140 BPM), or determined in real time,such as responsive to sensed physiological values.

In an embodiment of the present invention, control unit 20 is configuredto operate intermittently. Typically, upon each resumption of operation,control unit 20 sets the stimulation parameters to those in effectimmediately prior to the most recent cessation of operation. For someapplications, such parameters applied upon resumption of operation aremaintained without adjustment for a certain number of heartbeats (e.g.,between about one and about ten), in order to allow the heart rate tostabilize after resumption of operation.

For some applications, control unit 20 is configured to operateintermittently with gradual changes in stimulation. For example, thecontrol unit may operate according to the following “on”/“off” pattern:(a) “off” mode for 30 minutes, (b) a two-minute “on” periodcharacterized by a gradual increase in stimulation so as to achieve atarget heart rate, (c) a six-minute “on” period of feedback-controlledstimulation to maintain the target heart rate, and (d) a two-minute “on”period characterized by a gradual decrease in stimulation to return theheart rate to baseline. The control unit then repeats the cycle,beginning with another 30-minute “off” period.

In an embodiment of the present invention, control unit 20 is configuredto operate in an adaptive intermittent mode. The control unit sets thetarget heart rate for the “on” period equal to a fixed or configurablefraction of the average heart rate during the previous “off” period,typically bounded by a preset minimum. For example, assume that for acertain subject the average heart rates during sleep and during exerciseare 70 and 150 BPM, respectively. Further assume that the target heartrate for the “on” period is set at 70% of the average heart rate duringthe previous “off” period, with a minimum of 60 BPM. During sleep,stimulation is applied so as to produce a heart rate of MAX(60 BPM, 70%of 70 BPM)=60 BPM, and is thus applied with parameters similar to thosethat would be used in the simple intermittent mode describedhereinabove. Correspondingly, during exercise, stimulation is applied soas to produce a heart rate of MAX(60 BPM, 70% of 150 BPM)=105 BPM.

In an embodiment of the present invention, a heart rate regulationalgorithm used by control unit 20 has as an input a time derivative ofthe sensed heart rate. The algorithm typically directs the control unitto respond slowly to increases in heart rate and quickly to decreases inheart rate.

In an embodiment of the present invention, the heart rate regulationalgorithm utilizes sensed physiological parameters for feedback. Forsome applications, the feedback is updated periodically by inputting thecurrent heart rate. For some applications, such updating occurs atequally-spaced intervals. Alternatively, the feedback is updated byinputting the current heart rate upon each detection of a feature of theECG, such as an R-wave. In order to convert non-fixed R-R intervals intoa form similar to canonical fixed intervals, the algorithm adds thesquare of each R-R interval, thus taking into account the non-uniformityof the update interval, e.g., in order to properly analyze feedbackstability using standard tools and methods developed for canonicalfeedback.

In an embodiment of the present invention, control unit 20 implements adetection blanking period, during which the control unit does not detectheart beats. In some instances, such non-detection may reduce falsedetections of heart beats. One or both of the following techniques aretypically implemented:

-   -   Absolute blanking. An expected maximal heart rate is used to        determine a minimum interval between expected heart beats.        During this interval, the control unit does not detect heart        beats, thereby generally reducing false detections. For example,        the expected maximal heart rate may be 200 BPM, resulting in a        minimal detection interval of 300 milliseconds. After detection        of a beat, the control unit disregards any signals indicative of        a beat during the next 300 milliseconds.    -   Stimulation blanking. During application of a stimulation burst,        and for an interval thereafter, the control unit does not detect        heart beats, thereby generally reducing false detections of        stimulation artifacts as beats. For example, assume stimulation        is applied with the following parameters: a PPT of 5 pulses, a        pulse width of 1 ms, and a pulse repetition interval of 5 ms.        The control unit disregards any signals indicative of a beat        during the entire 25 ms duration of the burst and for an        additional interval thereafter, e.g., 50 ms, resulting in a        total blanking period of 75 ms beginning with the start of the        burst.

In an embodiment of the present invention, the heart rate regulationalgorithm is implemented using only integer arithmetic. For example,division is implemented as integer division by a power of two, andmultiplication is always of two 8-bit numbers. For some applications,time is measured in units of 1/128 of a second.

In an embodiment of the present invention, control unit 20 implements anintegral feedback controller, which can most generally be described by:K=K _(I) *∫e dtin which K represents the strength of the feedback, K_(I) is acoefficient, and ∫e dt represents the cumulative error. It is to beunderstood that such an integral feedback controller can be implementedin hardware, or in software running in control unit 20.

In an embodiment of such an integral controller, heart rate is typicallyexpressed as an R-R interval (the inverse of heart rate). Parameters ofthe integral controller typically include TargetRR (the target R-Rinterval) and TimeCoeff (which determines the overall feedback reactiontime).

Typically, following the detection of each R-wave, the previous R-Rinterval is calculated and assigned to a variable (LastRR). e (i.e., thedifference between the target R-R interval and the last measured R-Rinterval) is then calculated as:e=TargetRR−LastRRe is typically limited by control unit 20 to a certain range, such asbetween −0.25 and +0.25 seconds, by reducing values outside the range tothe endpoint values of the range. Similarly, LastRR is typicallylimited, such as to 255/128 seconds. The error is then calculated bymultiplying LastRR by e:Error=e*LastRR

A cumulative error (representing the integral in the above generalizedequation) is then calculated by dividing the error by TimeCoeff andadding the result to the cumulative error, as follows:Integral=Integral+Error/2^(TimeCoeff)The integral is limited to positive values less than, e.g., 36,863. Thenumber of pulses applied in the next series of pulses (pulses pertrigger, or PPT) is equal to the integral/4096.

The following table illustrates example calculations using a heart rateregulation algorithm that implements an integral controller, inaccordance with an embodiment of the present invention. In this example,the parameter TargetRR (the target heart rate) is set to 1 second(128/128 seconds), and the parameter TimeCoeff is set to 0. The initialvalue of Integral is 0. As can be seen in the table, the number ofpulses per trigger (PPT) increases from 0 during the first heart beat,to 2 during the fourth heart beat of the example. Heart Beat Number 1 23 4 Heart rate (BPM) 100 98 96 102 R-R interval (ms) 600 610 620 590 R-R(1/128 sec) 76 78 79 75 e (1/128 sec) 52 50 49 53 Limited e 32 32 32 32Error 2432 2496 2528 2400 Integral 2432 4928 7456 9856 PPT 0 1 1 2

In an embodiment of the present invention, the heart rate regulationalgorithm corrects for missed heart beats (either of physiologicalorigin or because of a failure to detect a beat). Typically, to performthis correction, any R-R interval which is about twice as long as theimmediately preceding R-R interval is interpreted as two R-R intervals,each having a length equal to half the measured interval. For example,the R-R interval sequence (measured in seconds) 1, 1, 1, 2.2 isinterpreted by the algorithm as the sequence 1, 1, 1, 1.1, 1.1.Alternatively or additionally, the algorithm corrects for prematurebeats, typically by adjusting the timing of beats that do not occurapproximately halfway between the preceding and following beats. Forexample, the R-R interval sequence (measured in seconds) 1, 1, 0.5, 1.5is interpreted as 1, 1, 1, 1, using the assumption that the third beatwas premature.

In an embodiment of the present invention, control unit 20 is configuredto operate in one of the following modes:

-   -   vagal stimulation is not applied when the heart rate of the        subject is lower than the low end of the normal range of a heart        rate of the subject and/or of a typical human subject;    -   vagal stimulation is not applied when the heart rate of the        subject is lower than a threshold value equal to the current low        end of the range of the heart rate of the subject, i.e., the        threshold value is variable over time as the low end generally        decreases as a result of chronic vagal stimulation treatment;    -   vagal stimulation is applied only when the heart rate of the        subject is within the normal of range of a heart rate of the        subject and/or of a typical human subjects;    -   vagal stimulation is applied only when the heart rate of the        subject is greater than a programmable threshold value, such as        a rate higher than a normal rate of the subject and/or a normal        rate of a typical human subject. This mode generally removes        peaks in heart rate; or    -   vagal stimulation is applied using fixed programmable        parameters, i.e., not in response to any feedback, target heart        rate, or target heart rate range. These parameters may be        externally updated from time to time, for example by a        physician.

In an embodiment of the present invention, the amplitude of the appliedstimulation current is calibrated by fixing a number of pulses in theseries of pulses (per cardiac cycle), and then increasing the appliedcurrent until a desired pre-determined heart rate reduction is achieved.Alternatively, the current is calibrated by fixing the number of pulsesper series of pulses, and then increasing the current to achieve asubstantial reduction in heart rate, e.g., 40%.

In embodiments of the present invention in which vagal stimulationsystem 18 comprises implanted device 25 for monitoring and correctingthe heart rate, control unit 20 typically uses measured parametersreceived from device 25 as additional inputs for determining the leveland/or type of stimulation to apply. Control unit 20 typicallycoordinates its behavior with the behavior of device 25. Control unit 20and device 25 typically share sensors 28 in order to avoid redundancy inthe combined system.

Optionally, vagal stimulation system 18 comprises a patient override,such as a switch that can be activated by the subject using an externalmagnet. The override typically can be used by the subject to activatevagal stimulation, for example in the event of arrhythmia apparentlyundetected by the system, or to deactivate vagal stimulation, forexample in the event of apparently undetected physical exertion.

FIG. 4 is a simplified illustration of an ECG recording 70 and exampletimelines 72 and 76 showing the timing of the application of a burst ofstimulation pulses 74, in accordance with an embodiment of the presentinvention. Stimulation is typically applied to vagus nerve 36 in aclosed-loop system in order to achieve and maintain the desired targetheart rate, determined as described above. Precise graded slowing of theheart beat is typically achieved by varying the number of nerve fibersstimulated, in a smaller-to-larger diameter order, and/or the intensityof vagus nerve stimulation, such as by changing the stimulationamplitude, pulse width, PPT, and/or delay. Stimulation with blocking, asdescribed herein, is typically applied during each cardiac cycle inburst of pulses 74, typically containing between about 1 and about 20pulses, each of about 1-3 milliseconds duration, over a period of about1-200 milliseconds. Advantageously, such short pulse durations generallydo not substantially block or interfere with the natural efferent orafferent action potentials traveling along the vagus nerve.Additionally, the number of pulses and/or their duration is sometimesvaried in order to facilitate achievement of precise graded slowing ofthe heart beat.

In an embodiment of the present invention (e.g., when the heart rateregulation algorithm described hereinabove is not implemented), to applythe closed-loop system, the target heart rate is expressed as aventricular R-R interval (shown as the interval between R₁ and R₂ inFIG. 4). The actual R-R interval is measured in real time and comparedwith the target R-R interval. The difference between the two intervalsis defined as a control error. Control unit 20 calculates the change instimulation necessary to move the actual R-R towards the target R-R, anddrives electrode device 26 to apply the new calculated stimulation.Intermittently, e.g., every 1, 10, or 100 beats, measured R-R intervalsor average R-R intervals are evaluated, and stimulation of the vagusnerve is modified accordingly.

In an embodiment, vagal stimulation system 18 is further configured toapply stimulation responsive to pre-set time parameters, such asintermittently, constantly, or based on the time of day.

Alternatively or additionally, one or more of the techniques ofsmaller-to-larger diameter fiber recruitment, selective fiber populationstimulation and blocking, and varying the intensity of vagus nervestimulation by changing the stimulation amplitude, pulse width, PPT,and/or delay, are applied in conjunction with methods and apparatusdescribed in one or more of the patents, patent applications, articlesand books cited herein.

In an embodiment of the present application, control unit 20 isconfigured to apply vagal stimulation when the heart rate of the subjectis below a threshold value, in order to increase the heart rate. Thethreshold value is typically determined for each subject, e.g., based onthe subject's hemodynamic needs and/or individual response to vagalstimulation. For example, for some subjects, the threshold value may beless than about 80 beats per minute, such as between 67 and 73 beats perminute. The threshold value is typically determined for each subject,e.g., based on the subject's hemodynamic needs and/or individualresponse to vagal stimulation. For some applications, the control unitis configured to apply fast intermittent stimulation, as definedhereinabove.

FIG. 5 is a graph illustrating experimental results measured inaccordance with an embodiment of the present invention. Vagalstimulation was applied to a conscious dog during alternating “on” and“off” periods having durations of 1 minute and 2 minutes, respectively.As can be seen in the graph, upon application of the vagal stimulationthe heart rate increased substantially.

In an embodiment of the present invention, control unit 20 is configuredto apply vagal stimulation (a) when the heart rate of the subject isabove a first threshold value, in order to reduce the heart rate, and(b) when the heart rate is below a second threshold value, which islower than the first threshold value, in order to increase the heartrate. Typically, the same stimulation is applied in both cases (a) and(b), and the stimulation has the desired decreasing or increasing effectdepending upon the heart rate, without specific configuration based onthe heart rate. The threshold values are typically determined for eachsubject, e.g., based on the subject's hemodynamic needs and/orindividual response to vagal stimulation. For typical subjects, thefirst threshold value is generally greater than about 80 BPM, and thesecond threshold value is generally less than about 80 BPM. In additionto the heart-rate-lowering benefits described hereinabove, stimulationusing the configuration of this embodiment generally has one or more ofthe following benefits: (a) maintenance of at least a minimal cardiacoutput, (b) improvements of the wellbeing of the subject when sleepingor at rest, (c) prevention of nocturnal dyspnea and polyuria, and (d)blood pressure regulation.

In an embodiment of the present invention, control unit 20 is configuredto apply vagal stimulation having a strength that is inversely related,e.g., inversely proportional, to a heart rate of the subject, i.e., asthe heart rate increases, the strength of the stimulation is decreased.For some applications, the control unit withholds applying the vagalstimulation when the heart rate exceeds a threshold value. The thresholdvalue, and the relationship between the strength of stimulation and theheart rate, are typically determined for each subject, e.g., based onthe subject's hemodynamic needs and/or individual response to vagalstimulation. For typical subjects, the threshold value is generallygreater than about 50 BPM. For some applications, the threshold value isset at a rate less than an average heart rate of the subject, such ascalculated by the control unit, or by a healthcare worker and input intothe control unit. For example, the threshold value may be set at anumber of BPM less than the average heart rate, or a percentage lessthan the average heart rate, e.g., about 1% to about 40% less.Alternatively, the threshold value is set equal to the average heartrate minus a certain number of standard deviations. For someapplications, such stimulation is applied during sleep, e.g., only ormostly during sleep. For some applications, a sleeping period of thepatient is determined by an accelerometer, electroencephalogram (EEG),or a clock.

Such a configuration generally results in the beneficial effects ofvagal stimulation that are not necessarily dependent on the heart-ratereduction effects of such stimulation. (See the above-cited article byVanoli E et al.) Such a configuration generally also results in animproved quality of life for the subject, because the heart rate isallowed to increase to meet the subject's physiological demands.

Such vagal stimulation is generally useful for treating conditions suchas AF, heart failure, atherosclerosis, restenosis, myocarditis,cardiomyopathy, post-myocardial infarct remodeling, and hypertension. Inaddition, such treatment is believed by the inventors to reduce the riskof sudden cardiac death in some patients (such as those withhypertrophic cardiomyopathy or congenital long QT syndrome).Furthermore, such treatment is believed by the inventors to bebeneficial for the treatment of some non-cardiovascular conditions, suchas an autoimmune disease, an autoimmune inflammatory disease, multiplesclerosis, encephalitis, myelitis, immune-mediated neuropathy, myositis,dermatomyositis, polymyositis, inclusion body myositis, inflammatorydemyelinating polyradiculoneuropathy, Guillain Barre syndrome,myasihenia gravis, inflammation of the nervous system, SLE (systemiclupus erythematosus), rheumatoid arthritis, vasculitis, polyarteritisnodosa, Sjogren syndrome, mixed connective tissue disease,glomerulonephritis, thyroid autoimmune disease, Graves' disease,Hashimoto's thyroiditis, sepsis, meningitis, a bacterial infection, aviral infection, a fungal infection, sarcoidosis, hepatitis, and portalvein hypertension, obesity, constipation, irritable bowel syndrome,pancreatitis, type I diabetes, anemia, and type II diabetes, and toincrease the glomerular filtration rate (GFR) in patients such as thosesuffering from kidney failure.

Such vagal stimulation is also beneficial for treating some conditionsor under some circumstances in which heart rate reduction is notindicated or is contraindicated. For example, such vagal stimulation istypically appropriate:

-   -   for treating heart failure patients that suffer from bradycardia        when taking beta-blockers;    -   at nighttime, when heart rate is naturally lower;    -   during exercise, such as when the heart rate is already within a        desired range and further decreases may reduce exercise        tolerance;    -   for patients receiving heart-rate lowering drugs, who have        achieved a heart rate within a desired range prior to beginning        vagal stimulation, and therefore would not benefit from further        heart rate reduction;    -   for patients suffering from low cardiac output, for whom heart        rate reduction may further reduce cardiac output;    -   during acute myocardial infarction with cardiogenic shock;    -   for patients who experience discomfort or a reduction in        exercise capacity when the heart rate is reduced; and    -   for patients having a tendency towards bradycardia when        receiving vagal stimulation.

In an embodiment, such inversely-proportional stimulation is applied inrespective bursts of pulses in each of a plurality of cardiac cycles ofthe subject, and synchronized with the cardiac cycle of the subject. Forsome applications, the stimulation is configured to minimize theheart-rate-lowering effects of the stimulation, for example by applyingsuch synchronized stimulation using one or more of the followingparameters:

-   -   Timing of the stimulation: delivery of the burst of pulses        begins after a variable delay following each P-wave, the length        of the delay equal to between about two-thirds and about 90% of        the length of the patient's cardiac cycle. Such a delay is        typically calculated on a real-time basis by continuously        measuring the length of the patient's cardiac cycle.    -   Pulse duration: each pulse typically has a duration of between        about 200 microseconds and about 2.5 milliseconds for some        applications, or, for other applications, between about 2.5        milliseconds and about 5 milliseconds.    -   Pulse amplitude: the pulses are typically applied with an        amplitude of between about 0.5 and about 5 milliamps, e.g.,        about 1 milliamp.    -   Pulse repetition interval: the pulses within the burst of pulses        typically have a pulse repetition interval (the time from the        initiation of a pulse to the initiation of the following pulse)        of between about 2 and about 10 milliseconds, e.g., about 2.5        milliseconds.    -   Pulse period: the burst of pulses typically has a total duration        of between about 0.2 and about 40 milliseconds, e.g., about 1        millisecond.    -   Pulses per trigger (PPT): the burst of pulses typically contains        between about 1 and about 10 pulses, e.g., about 2 pulses.    -   Vagus nerve: the left vagus nerve is typically stimulated in        order to minimize the heart-rate-lowering effects of vagal        stimulation.    -   Duty cycle: stimulation is typically applied only once every        several heartbeats, or once per heartbeat, when a stronger        effect is desired.    -   On/off status: for some applications, stimulation is always        “on”, i.e., constantly applied (in which case, parameters closer        to the lower ends of the ranges above are typically used). For        other applications, on/off cycles vary between a few seconds to        several dozens of seconds, e.g., “on” for about 36 seconds,        “off” for about 120 seconds, “on” for about 3 seconds, “off” for        about 9 seconds.

For some applications, one or more of these minimal heart-rate-loweringparameters are used for stimulation in other embodiments of the presentinvention.

In an embodiment of the present invention, control unit 20 comprises oris coupled to an implanted device 25 for monitoring and correcting theheart rate, such as an implantable cardioverter defibrillator (ICD) or apacemaker (e.g., a bi-ventricular or standard pacemaker). For example,implanted device 25 may be incorporated into a control loop executed bycontrol unit 20, in order to increase the heart rate when the heart ratefor any reason is too low.

In an embodiment, at least one of control unit 20 and/or a control unitof the ICD or pacemaker is configured to coordinate an aspect of itsoperation with an aspect of operation of the other control unit. Forexample, the aspect of the operation may be an aspect of timing of theoperation. Typically, control unit 20 and the control unit of the ICD orpacemaker are not under common control, i.e., an additional controlleris not provided for coordinating the aspect of operation. For someapplications, control unit 20 or the control unit of the ICD isconfigured to coordinate the aspect of operation without communicatingwith the other control unit. Alternatively, for some applications, thecontrol units directly communicate with each other in order tocoordinate the aspect of operation. For some applications, control unit20 is configured to apply vagal stimulation with stimulation and/orfeedback parameters that reduce the likelihood of the vagal stimulationcausing the ICD or pacemaker to falsely detect arrhythmia. Alternativelyor additionally, for some applications, control unit 20 is configured toapply vagal stimulation with stimulation and/or feedback parameters thatreduce the likelihood of the occurrence of a “tug-of-war” between vagalstimulation system 18 and the ICD or pacemaker.

According to a first technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD or pacemaker,control unit 20 is configured to apply vagal stimulation in bursts thatare synchronized with the cardiac cycle of the subject. The control unitapplies each burst during the refractory period of the heart and the ICDblanking period (the period during which the ICD does not attempt todetect the next heart beat), i.e., typically beginning shortly afterdetection of each QRS complex (e.g., within between 0 and about 100milliseconds after detection), as detected by the ICD or the pacemaker,or by stimulation system 18. The control unit typically completesapplication of each burst within about 100 milliseconds of the detectionof the QRS complex. For some applications, the control unit determinesthe occurrence of the QRS complex based on the detection of the P-waveimmediately preceding the QRS complex.

According to a second technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, the ICD isconfigured to generate a communication signal during application ofstimulation to the heart. Control unit 20 is configured to receive thesignal, and, responsive thereto, to withhold applying vagal stimulationuntil the ICD completes its application of stimulation. For someapplications, control unit 20 waits a certain period of time after theICD completes stimulation, before again applying vagal stimulation.

According to a third technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with ICD, the ICD isconfigured to generate a communication signal upon detection ofventricular fibrillation (VF) or ventricular tachycardia (VT). Controlunit 20 is configured to receive the signal, and, responsive thereto, towithhold applying vagal stimulation until the ICD indicates that the VFor VT has resolved. Alternatively or additionally, control unit 20 isconfigured to directly detect the VF, VT, and/or SVT.

According to a fourth technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, stimulationsystem 18 and the ICD are each assigned a discrete range of heart ratesat which to apply their respective stimulations. For example, the ICDmay be configured to defibrillate, attempt rapid pacing, or pace only atheart rates greater than about 190 BPM or less than about 60 BPM, whilecontrol unit 20 is configured to apply vagal stimulation only when theheart rate is between about 70 and about 180 BPM.

According to a fifth technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, the ICD isconfigured to identify the stimulus artifact of the vagal stimulation,and to treat this artifact as noise.

According to a sixth technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, stimulationsystem 18 is configured to have a maximum allowable number of PPT (e.g.,2), which typically results in a stimulation period that is too brieffor the ICD to detect.

According to a seventh technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, the ICD isconfigured to generate a communication signal at every R-wave detection.Control unit 20 is configured to receive the signal, thereby avoidingany potential discrepancy between control unit 20 and the ICD regardingthe precise timing of each R-wave. Such synchronization also enablesdetermination of a common reference time point in each cardiac cycle.For example, the ICD may be configured to use this common referencepoint as the starting time for a blanking period, as described in theninth technique hereinbelow.

According to an eighth technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, control unit20 is configured to generate a communication signal to the ICD duringeach application of vagal stimulation. The ICD receives the signal, and,responsively thereto, withholds applying stimulation while the controlunit is applying vagal stimulation.

According to a ninth technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, the ICD isconfigured to have an extended blanking period, during which the ICDdoes not attempt to detect the next heart beat. Control unit 20 isconfigured to apply vagal stimulation only during this extended blankingperiod. Because the ICD does not sense during this period, the ICDcannot falsely identify the vagal stimulation as a feature of thecardiac cycle, such as an R-wave.

According to a tenth technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD: (a) the ICD isconfigured to detect an occurrence of arrhythmia only if the arrhythmiacontinues for a certain number (X) of consecutive heart beats, and (b)control unit 20 is configured to not stimulate during more than acertain number (Y) of consecutive heart beats, where Y is less than X.

According to an eleventh technique for reducing the likelihood of falsedetection of arrhythmia and/or a tug-of-war with the ICD, control unit20 and/or the ICD is programmed with a flag, which indicates to thedevice that it must take into consideration the presence of the otherdevice. If the flag indicates that no other device is present,techniques for avoiding conflicts between the devices do not need to beemployed. Control unit 20 and the ICD typically communicate with oneanother in order to set the flag.

For some applications, two or more of these techniques for reducing thelikelihood of false detection of arrhythmia and/or a tug-of-war with theICD are used in combination.

In an embodiment, upon detection of suspected arrhythmia, either by theICD or by stimulation system 18, control unit 20 applies vagalstimulation in order to reduce the ventricular rate. The ICD isconfigured to apply defibrillation to the heart if the vagal stimulationis not sufficiently effective in reducing the ventricular rate.

In an embodiment of the present invention, control unit 20 is configuredto classify an arrhythmia detected by the ICD or system 18. Ventriculartachycardia (VT) and ventricular fibrillation (VF) originate in theventricles. Because vagal stimulation affects the SA and AV nodes, vagalstimulation does not have a meaningful effect on heart rate during VT orVF. To classify a detected arrhythmia, control unit 20 applies vagalstimulation, and determines its effect on heart rate and/or heart ratevariability. If the vagal stimulation affects heart rate or variability,control unit 20 makes a determination that the arrhythmia probably didnot originate in the ventricles, and therefore is probably neither VTnor VF.

In an embodiment of the present invention, control unit 20 implementsone or more counters, either in software running the control unit, or inhardware. Such counters include, but are not limited to:

-   -   a counter that counts the number of stimulations, e.g., the        number of bursts, applied to the vagus nerve during a certain        period of time;    -   a counter that counts the total number of pulses applied to the        vagus nerve during a certain period of time. For example, if        control unit 20 applies 2 bursts each having 3 PPT, the counter        counts 6 pulses; and/or    -   a counter that counts the number of detected heart beats during        a certain period of time.

For some applications, such as when control unit 20 operates usingfeedback, as described hereinabove, an average number of pulses perstimulation burst (i.e., average PPT) is calculated by dividing thetotal number of pulses applied in a given period by the number ofstimulation bursts applied in the period. This calculation is typicallyperformed by control unit 20, or by a physician using the data generatedby the counters. The average PPT is an indication of the strength ofstimulation the control unit needed to apply, based on feedback, inorder to maintain the heart rate at the desired target rate. A physicianmay use this indication to adjust parameters of the stimulation. Forexample, if the physician believes the average PPT is too high, he mayincrease the strength of the stimulation by adjusting another parameter,such as the amplitude of the applied signal, which should result in alower average PPT. Alternatively, the physician may adjust the targetheart rate in order to cause a lower average PPT.

For some applications, control unit 20 monitors in real time the averagePPT. For example, a sudden increase in average PPT (calculated over anappropriate time period) may be interpreted as a possible technicalfailure or change in the physiological state of the subject (e.g.,decompensation of the underlying disease). It is to be appreciated thattasks described herein as being performed by a physician may also beperformed by a suitably-configured algorithm.

In an embodiment of the present invention, control unit 20 operatesusing feedback, as described hereinabove, and is configured to target anumber of pulses applied during each burst of stimulation, responsive tothe feedback. Such feedback sometimes results in variations in theaverage number of pulses per burst. In this embodiment, control unit 20is configured to monitor the average number of pulses per burst in agiven time period. Such monitoring is performed either periodically orsubstantially continuously. If the average number of pulses per burstexceeds a maximum threshold value over the given time period, thecontrol unit modifies one or more stimulation or feedback parameters,such that the average number of pulses per burst declines below themaximum threshold value. For example, the maximum threshold value may bebetween about 2 and about 4 pulses per burst, e.g., about 3 pulses perburst. Appropriate parameters for modification include, but are notlimited to, (a) one or more of the feedback parameters, such as thetarget heart rate (e.g., TargetRR), and/or the feedback integralcoefficient, and/or (b) one or more stimulation parameters, such asstimulation amplitude, and pulse width, and/or maximum number of pulseswithin a burst. Alternatively or additionally, for some applications, ifthe average falls below a minimum threshold value, the control unitmodifies one or more stimulation or feedback parameters, such that theaverage number of pulses per burst increases above the minimum thresholdvalue.

In an embodiment of the present invention, control unit 20 operatesusing feedback, as described hereinabove, which results in a variablenumber of bursts per heart beat and/or per unit time. (For example, aburst may be applied every 1-60 heart beats, or every 0.3-60 seconds, asdictated by a feedback algorithm.) Such feedback sometimes results inhigh- and/or low-frequency variations in the duty cycle. Control unit 20is configured to monitor the average duty cycle in a given time period.Such monitoring is performed either periodically or substantiallycontinuously. If the average exceeds a maximum threshold value, thecontrol unit modifies one or more stimulation or feedback parameters,such that the average duty cycle declines below the maximum thresholdvalue. Appropriate parameters for modification include, but are notlimited to, the target heart rate (e.g., TargetRR), the feedbackintegral coefficient, stimulation amplitude, pulse width, and maximumnumber of pulses within a burst. Alternatively or additionally, for someapplications, if the average falls below a minimum threshold value, thecontrol unit modifies one or more stimulation or feedback parameters,such that the average duty cycle increases above the maximum thresholdvalue. For some applications, control unit 20 implements the techniquesof this embodiment in combination with the techniques for monitoring theaverage number of pulses per burst described above.

In an embodiment of the present invention, in which control unit 20 isconfigured to operate in intermittent “on”/“off” periods, as describedhereinabove, the monitored average duty cycle is used in combinationwith the ratio of the “on” duration to “off” duration in order todetermine the magnitude of the heart-rate-lowering effect of the vagalstimulation. A duty cycle less than the “on”/“off” ratio indicates thatthe stimulation is causing lowering of the heart rate, while a dutycycle equal to the “on”/“off” ratio indicates that no such lowering ofthe heart rate is occurring. Typically, control unit 20 monitors theaverage duty cycle over a time period that includes at least one full“on” period and one full “off” period, such as several “on” and “off”periods. For example, assume that control unit 20 is configured tostimulate in alternating “on” periods of 60 seconds and “off” periods of120 seconds. During the “on” periods the average heart rate is 60 BPM,and during the “off” periods the average heart rate is 120 BPM. Usingthese exemplary values, the duty cycle would be 60 bursts/300 heartbeats=0.2, and the “on”/“off” ratio would be 60 seconds/180seconds=0.33. The duty cycle is less than the “on”/“off” ratio,indicating that the stimulation is effectively lowering the heart rate.If, on the other hand, the heart rate remained 120 BPM during the “on”periods, the duty cycle would be 120 bursts/360 heart beats=0.33, whilethe “on”/“off” ratio would remain 0.33. This equality would indicatethat the stimulation is having no heart-rate-lowering effect.

In an embodiment of the present invention, control unit 20 operatesusing feedback, as described hereinabove, and is configured to set amaximum allowable level of stimulation. Control unit 20 does not applystimulation beyond this maximum level even if the feedback algorithmcalls for increased stimulation. Typically, the maximum allowable levelof stimulation is expressed as an average amount of energy over a timeperiod of at least about 1 minute, e.g., about 30 minutes. A physiciantypically sets the maximum level based on considerations such aspossible side effects of stimulation, safety, and physiologicaltolerance. Alternatively or additionally, the maximum level ispreconfigured based on generally-applicable safety considerations. Themaximum level of stimulation is typically implemented by setting amaximum level (typically predetermined) of one or more of the followingparameters:

-   -   Maximum PPT, e.g., between about 2 and about 20, such as about        8.    -   Maximum duty cycle, e.g., between about 5% and about 100%, e.g.,        20%, in a time frame of between about 5 seconds and several        weeks, e.g., one day.    -   Maximum continuous stimulation period, expressed in either heart        beats or units of time.    -   Peak power consumption, e.g., about 1 watt.

A physician may increase one or more of these values (e.g., maximumPPT), for example, if a subject adapts to stimulation, or decrease oneor more of these values (e.g., maximum PPT) if side effects occur. Inthe event that feedback causes the value of one or more of theseparameters to exceed the maximum value (e.g., the duty cycle to exceed athreshold value such as 50%, or the continuous stimulation periodexceeds a threshold value such as 5 hours), control unit 20automatically, or a physician manually, may, for example, increase thetarget heart rate, or apply fast intermittent stimulation (as definedhereinabove), in order to reduce the value of the parameter to anappropriate level below the maximum value. Alternatively oradditionally, when feedback causes the value of one or more of theseparameters to exceed the maximum, control unit 20 may notify the subjectand/or the physician, so that the subject may seek medical care, and/orthe physician may adjust one or more of the stimulation parameters.

In an embodiment of the present invention, control unit 20 is configuredto gradually ramp the commencement and/or termination of stimulation. Inorder to achieve the gradual ramp, the control unit is typicallyconfigured to gradually modify one or more stimulation parameters, suchas those described hereinabove, e.g., pulse amplitude, number of pulses,PPT, pulse frequency, pulse width, “on” time, and/or “off” time.Terminating stimulation gradually, rather than suddenly, may reduce thelikelihood of a rebound acceleration of heart rate that sometimes occursupon termination of vagal stimulation. As appropriate, one or more ofthese parameters is varied by less than 50% of the pre-termination valueper heart beat, or less than 5% per heart beat, in order to achieve thegradual ramp.

In an embodiment of the present invention, control unit 20 is configuredto gradually increase the strength of stimulation according to apredetermined schedule. Such a gradual increase is typically appropriateduring the first several days of use of system 18 by a new subject.Subjects sometimes experience discomfort and/or pain during theirinitial exposure to stimulation. Such discomfort and/or pain typicallyceases after an accommodation period of several days. By graduallyincreasing stimulation from an initially low level, control unit 20generally prevents such discomfort and/or pain. For example, thestrength of stimulation may be increased less than 50% per hour, or lessthan 10% per day. The control unit is typically configured to increasethe strength of stimulation by adjusting one or more stimulationparameters, such as those described hereinabove, e.g., the amplitude ofthe applied signal.

For some applications, system 18 is configured to allow the subject tomanually control the ramp-up of stimulation, e.g., by selecting when thesystem proceeds to successive levels of stimulation, and/or byrequesting the system to return to a previous level of stimulation.

In an embodiment, these techniques for gradually increasing the strengthof stimulation are applied to stimulation of nerves other than the vagusnerve, such as other nerve stimulation is known in the art.

In an embodiment of the present invention, control unit 20 is configuredto store a series of one or more physiological parameters measured bysystem 18, in response to receiving an external command to store theparameters. This allows a physician to specify precisely when to beginrecording the series, which enables the physician to monitor acutechanges in the subject. For example, in order to test external and/orstimulation effects on heart rate, the physician may begin recording theseries prior to: (a) instructing the subject to change his position, (b)applying carotid massage to the subject, (c) adjusting stimulationand/or feedback parameters, and/or (d) applying stimulation to thesubject using stimulation parameters the physician would like toevaluate. For some applications, the recorded physiological parametersinclude (a) R-R intervals, as described hereinabove, (b) systolic anddiastolic blood pressures, and/or (c) at least one feature of anelectrocardiogram (ECG). For some applications, control unit 20 isconfigured to store the physiological parameters over a predefinedperiod of time, or for a predetermined number of values of theparameters. In an embodiment, control unit 20 is configured to accept anexternal command to begin recording the series of parameters at a timein the future, e.g., at a certain time of day, or after a certain delay.

In an embodiment of the present invention, a subject's reaction tostimulation using stimulation system 18 is evaluated while the subjectexercises. The subject typically performs the exercise using exerciseequipment, such as a treadmill. For some applications, a physicianinitially sets stimulation parameters of system 18 while the subject isat rest with a relatively low heart rate. The subject then performs theexercise, which increases the heart rate to a level the physicianconsiders to be at least the maximum level the subject is likely toexperience during normal daily activity. Using feedback, as describedhereinabove, control unit 20 reacts to the increased heart rate bymodifying one or more stimulation parameters to increase the level ofstimulation. This increased level of stimulation represents the maximumstimulation likely to be applied to the subject during use of system 18.Therefore, such stimulation is likely to produce the maximum potentialside effects of stimulation that the subject may experience. Thephysician evaluates the subject at this increased level of stimulationin order to assess these side effects and the tolerance of the subjectto stimulation by system 18. Based on this evaluation, the physician maymodify the stimulation parameters, or make other decisions regarding thesubject's treatment.

Alternatively or additionally, stimulation parameters are adjustedduring the exercise in order to achieve the heart rate at which theheart is maximally effective. Such effectiveness may be measured, forexample, by peak performance, peak pO₂, or other indicators of hearteffectiveness known in the art.

In an embodiment of the present invention, for applications in whichcontrol unit 20 is configured to apply vagal stimulation intermittently,as described hereinabove, the control unit begins the stimulation withan “off” period, rather than with an “on” period. As a result, a delayhaving the duration of an “off” period occurs prior to beginningstimulation. Alternatively or additionally, whether or not configured toapply stimulation intermittently, control unit 20 is configured to delaybeginning the application of stimulation for a certain time period(e.g., a pseudo-randomly determined time period, or a predeterminedfixed period of time, such as about 5 seconds) after receiving anexternal command to apply the stimulation. The use of these delayingtechniques generally reduces a subject's anticipation of any pain ordiscomfort that he may associate with stimulation, and disassociates thesensations of stimulation from the physician and/or an external controldevice such as a wand.

In an embodiment of the present invention, a method for facilitating thedetermination of vagal stimulation parameters comprises: (a) applyingintermittent vagal stimulation, as described hereinabove, during acalibration period of time that includes a plurality of differentnaturally-occurring heart rates; (b) for each “on” period and each “off”period, calculating an average heart rate during the period; and (c)segmenting the average heart rates during the “off” periods into aplurality of heart rate ranges; and (d) separately evaluating the effectof vagal stimulation on heart rates within each heart rate range, bycalculating an average difference in average heart rate between “on” and“off” periods within the given heart rate range. This analysis is usedto determine separate stimulation and feedback parameters for each rangeof heart rates.

FIG. 6 is a graph illustrating experimental results measured inaccordance with an embodiment of the present invention. Intermittentvagal stimulation was applied to a conscious dog during alternating “on”and “off” periods having durations of 1 minute and 2 minutes,respectively. Each point on the graph (indicated by an “x”) represents asingle stimulation period, including a single “on” period and the “off”periods immediately preceding and following the “on” period. They-coordinate of each point indicates the average R-R interval during therespective “on” period, and the x-coordinate indicates the average R-Rinterval during the respective “off” periods immediately preceding andfollowing the “on” period. As can be seen in the graph, nearly all ofthe points lie above the x=y line, indicating that the vagal stimulationlowered the heart rate during the stimulation “on” periods more thannon-stimulation lowered the heart rate during the correspondingnon-stimulation “off” periods. The graph of FIG. 6 thus presents anoverall view of the reaction of the dog to vagal stimulation. In anembodiment of the present invention, a graph such as that shown in FIG.6 is generated in order to enable (a) visualization and/or assessment ofthe effectiveness of vagal stimulation at various heart rates, and,optionally, (b) modification of applied signal parameters to improve theresponse at certain heart rates.

In an embodiment of the present invention, in which control unit 20(FIG. 1) is implantable, vagal stimulation system 18 further comprisesan external monitoring unit (not shown in figures). For someapplications, the monitoring unit is adapted to record the timing of theapplication of vagal stimulation, such as the timing of the commencementand/or termination of “on” and “off” periods. Typically, the monitoringunit performs this recording in real-time while system 18 applies thevagal stimulation. (In some hardware configurations, it is not feasibleto record such data in implantable control unit 20 because the controlunit lacks sufficient memory.) For some applications, in order toperform the recording, the monitoring unit monitors an electrocardiogram(ECG) of the subject, and detects an artifact in the ECG that isindicative of application of the stimulation signal. For someapplications, one or more ECG monitoring patches are placed on thesurface of the skin in a vicinity of electrode device 26. Forstimulation that is synchronized with a feature of the subject's cardiaccycle (e.g., with an R-wave), the monitoring unit typically attempts todetect the stimulation artifact only at the known appropriate delay fromthe feature of the cardiac cycle, so as to reduce the likelihood of afalse positive detection of stimulation. Alternatively, a dedicatedrecording channel of the ECG is assigned to record the electricalpotential differences between the two sides of the neck, which detectssubstantially only the stimulation artifact, rather than the ordinaryECG signal.

Alternatively, in order to facilitate the recording, implantable controlunit 20 is adapted to transmit a communication signal to the externalmonitoring unit upon each application of vagal stimulation. Typically,control unit 20 sends the communication signal wirelessly;alternatively, the signal is sent over wires to the monitoring unit.

For some applications, the intermittent vagal stimulation is appliedwith “on” periods having a duration of between about 45 and about 75seconds each, e.g., about 1 minute each, and “off” periods having aduration of between about 90 and about 150 seconds each, e.g., about 2minutes each. Alternatively or additionally, the intermittent vagalstimulation is applied with “off” periods having a duration of betweenabout 1.2 and about 3.5 times greater than the “on” periods, e.g.,between about 1.5 and about 2.5 times greater than the “on” periods. Inorder to include the plurality of different naturally-occurring heartrates, the calibration period typically includes at least severalhundred “on” and “off” periods. For example, the calibration period maybe about 24 hours. Alternatively, the calibration period is shorter, andincludes sub-periods of rest, exercise, and recovery from exercise, inorder to ensure the inclusion of the plurality of differentnaturally-occurring heart rates. For example, for at least part of thecalibration period the subject may be subjected to an exercise test(e.g., a stress test), such as by using exercise equipment, e.g., atreadmill.

In an embodiment of the present invention, control unit 20 comprises oris coupled to an implanted device 25, such as an ICD, that is configuredto apply antitachycardia pacing in order to treat ventriculartachycardia. Control unit 20 is configured to apply vagal stimulation inconjunction with antitachycardia pacing.

In an embodiment of the present invention, control unit 20 is adapted to(a) receive a sensed physiological parameter of the subject from ECGmonitor 24 and/or physiological sensors 28, and (b) responsively to thesensed physiological parameter, configure the applied stimulation totreat bundle branch block of the subject.

Reference is made to FIG. 7, which is a flow chart that schematicallyillustrates a method for treating life-threatening arrhythmia (LTA), inaccordance with an embodiment of the present invention. In thisembodiment, control unit 20 comprises or is coupled to implanted device25, such as an ICD or pacemaker, that is configured to applyanti-arrhythmic therapy, such as rapid pacing, defibrillation, and/orcardioversion. Control unit 20 is adapted to detect the LTA (forexample, VF, VT, or fast VT), and evaluate the severity of the LTA. Upondetection, the control unit attempts to resolve the LTA by selecting theoptimal therapy for the LTA, responsively to the evaluation. Typically,the control unit is configured to: (a) preferably, drive electrodedevice 26 to apply parasympathetic stimulation, and (b) less preferably,drive implanted device 25 to apply anti-arrhythmic therapy if suchanti-arrhythmic therapy is indicated, e.g., if parasympatheticstimulation has not successfully resolved the LTA, or is deemed unlikelyto resolve the LTA. The techniques of this embodiment thus generallyreduce the use of anti-arrhythmic therapy, which is often painful orunpleasant for patients.

Turning to the flow chart, at a monitor step 100, control unit 20monitors heart 30 by receiving one or more sensed parameters, e.g.,R-waves, such as detected by ECG monitor 24. At an LTA detection step102, control unit 20 determines whether an LTA is occurring, such as byusing techniques described herein or in one or more articles, patents,and/or patent applications incorporated herein by reference, orotherwise known in the art. If an LTA is not detected, control unit 20continues monitoring heart 30 at monitor step 100.

If, on the other hand, control unit 20 detects an LTA, at aparasympathetic stimulation step 104 the control unit appliesparasympathetic stimulation to subject 31 in an attempt to resolve theLTA without application of anti-arrhythmic therapy. The control unittypically, but not necessarily, applies the parasympathetic stimulationusing vagal stimulation techniques described herein or in one or morearticles, patents, and/or patent applications incorporated herein byreference, or otherwise known in the art.

The control unit determines whether the LTA has been resolved, at an LTAresolution check step 106. If the LTA has been resolved, the controlunit returns to monitor step 100. Otherwise, at an evaluation check step108, the control unit determines whether anti-arrhythmic therapy isindicated, e.g., that parasympathetic stimulation is unlikely to resolvethe LTA. To make this determination, the control unit typicallyconsiders such factors as the severity of the LTA, trends in theseverity of the LTA, the time from the onset of the LTA, and theduration of the parasympathetic stimulation. For example, if the timefrom the onset of the LTA exceeds a certain threshold value, the controlunit may determine that anti-arrhythmic therapy is indicated. (For someapplications, the control unit modifies, e.g., reduces, the thresholdvalue on subsequent iterations through step 106.) Alternatively, thecontrol unit may, for example, determine that continued parasympatheticstimulation is indicated if the heart rate is less than an upperthreshold indicative of continuing LTA, but greater than a lowerthreshold indicative of resolution of all arrhythmia (e.g., the upperthreshold may be about 200 BMP, and the lower threshold may be about 160BMP). If the control unit determines that anti-arrhythmic therapy isindicated, the control unit applies anti-arrhythmic therapy at ananti-arrhythmic therapy step 110. On the other hand, if the control unitdetermines that anti-arrhythmic therapy is not indicated, the controlunit continues applying parasympathetic stimulation at step 104. Forsome applications, the control unit modifies at least one parameter ofsuch parasympathetic stimulation during some or all of the repetitionsof step 104.

Reference is made to FIG. 8, which is a flow chart that schematicallyillustrates another method for treating life-threatening arrhythmia(LTA), in accordance with an embodiment of the present invention. Thismethod is similar to the method described hereinabove with reference toFIG. 7, except that according to this method control unit 20 applieschronic parasympathetic stimulation even in the absence of an LTA. At aparasympathetic stimulation and monitor step 120, the control unitapplies the chronic parasympathetic stimulation and monitors heart 30.The control unit determines whether an LTA is occurring, at an LTAdetection step 122. If an LTA is not detected, control unit 20 continuesmonitoring heart 30 at parasympathetic stimulation and monitor step 120.

If, on the other hand, control unit 20 detects an LTA, the control unitmodifies at least one parameter of the parasympathetic stimulation (forexample, in order to modify, e.g., increase, a strength of thestimulation), at a modify parameter step 124. The control unit continuesto apply the parasympathetic stimulation, using the new parameter, at aparasympathetic stimulation step 126. At an LTA resolution check step128, the control unit determines whether the LTA has been resolved. Ifthe LTA has been resolved, the control unit returns to parasympatheticstimulation and monitor step 120. Otherwise, at an evaluation check step130, the control unit determines whether anti-arrhythmic therapy isindicated, such as by using one or more of the techniques describedhereinabove with reference to evaluation check step 108 of FIG. 7. Ifthe control unit determines that anti-arrhythmic therapy is indicated,the control unit applies anti-arrhythmic therapy at an anti-arrhythmictherapy step 132. On the other hand, if the control unit determines thatanti-arrhythmic therapy is not indicated, the control unit returns tostep 124, at which the control unit again modifies at least oneparameter of the parasympathetic stimulation. (Alternatively, for someapplications, the control unit determines that no parameters need to bemodified, and therefore skips step 124 and proceeds to step 126.)

Some embodiments of the present invention combine vagal stimulation withother methods of electric therapy for the heart. Among these othermethods are pacing, anti-arrhythmia pacing, defibrillation and cardiacresynchronization therapy (CRT).

CRT is typically indicated for patients with intrinsic conductionabnormalities, specifically with bundle branch blocks or delays. Onetype of CRT apparatus comprises a control unit and an electricstimulator connected to an atrial sensing lead and two ventricularpacing leads, one for each ventricle. The pacing lead for the leftventricle is usually placed over the left ventricle through the coronarysinus, while the right ventricle lead is placed within the rightventricle. The control unit senses an atrial depolarization and appliestimed pacing signals to both ventricles. Typically the pacing signal tothe right ventricle is applied around 110 ms after atrialdepolarization, and the pacing signal to the left ventricle followswithin about 50 ms.

At the time of implantation of a CRT device, echocardiographicmeasurements are typically used to find suitable timing settings toprovide improved cardiac performance. The timing settings typically varyas a function of heart rate, and the beneficial effect of CRT alsotypically varies as a function of heart rate.

It has been observed with respect to CRT that the pacing frequencyshould be faster than the normal heart rate (otherwise the naturalrhythm or the natural conduction may prevail). Thus CRT is typicallylimited to patients in whom the conduction times and/or heart rate areslow.

It has also been observed with respect to CRT that the applied pacingsignal does not always propagate through natural conduction pathways.

Some embodiments of the present invention provide a combination of (a)biventricular pacing with (b) sensing in any one or more of the fourchambers, to facilitate control of the timing of induced contractions.In the context of the present patent application and in the claims, thisis also referred to as cardiac resynchronization therapy.

Vagal stimulation has been shown to reduce sinus rate, prolongconduction through the AV node, and alter conductance of other pathwayswithin the heart.

In some embodiments of the present invention, CRT and vagal stimulationare both applied to a patient as part of a treatment protocol.Typically, the vagal stimulation is applied using techniques describedhereinabove, and the CRT and vagal stimulation achieve a synergisticeffect. For some applications, the CRT improves an effect of the vagalstimulation. Alternatively or additionally, the vagal stimulationimproves an effect of the CRT. For some applications, use of vagalstimulation allows CRT to be applied to a patient otherwise not eligibleor suitable for CRT. For some applications, use of CRT allows vagalstimulation to be applied to a patient otherwise not eligible orsuitable for vagal stimulation. In an embodiment, one or more of thebenefits described in this paragraph are facilitated by at least one ofthe following:

-   -   Vagal stimulation is configured to prolong AV conduction time,        in combination with CRT.    -   Vagal stimulation is configured to prolong RR interval, in        combination with CRT.    -   Vagal stimulation and CRT are applied using separate devices not        under common control.    -   Vagal stimulation and CRT are each configured to improve cardiac        performance.

In some embodiments, CRT is applied in order to modify an effect ofvagal stimulation. Vagal stimulation may cause transient conductiondelays, especially AV conduction delays, even in patients with no“natural” conduction disturbances. Applying CRT together with vagalstimulation typically reduces this effect of vagal stimulation, thusimproving the outcome of the patient.

In some configurations, vagal stimulation reduces atrial contractionforce, thus changing the filling curve of the ventricles. In such acase, the optimal timing of ventricular contraction is typicallydifferent from the optimal timing without vagal stimulation. By usingCRT, different AV timings can be set for periods with vagal stimulationcompared to periods without such stimulation. This typically improvescardiac performance during vagal stimulation.

In some embodiments, vagal stimulation is used to improve CRT. Vagalstimulation may be used, for example, to slow conduction times, thusallowing resynchronization therapy in patients with shorter thanoptimal-for-CRT AV delays and/or with shorter than optimal-for-CRTintracardiac conduction times.

In some embodiments, in patients in whom a portion of the cardiacconduction is too fast and other portions are too slow, vagalstimulation is used to prolong the conduction time of some or allpathways, facilitating improvement of cardiac performance by CRT.

For some applications, vagal stimulation brings the heart rate to aheart rate at which the benefit of CRT is improved, thus enhancing theefficacy of CRT.

In some embodiments, vagal stimulation, by itself, is used asresynchronization therapy. In this context, vagal stimulation may beused as a sole therapy to optimize AV conduction time, and to bringabout synchronization of cardiac contraction by the differential effectof vagal stimulation on each ventricle. The intensity and timing ofvagal stimulation together with the specific site of stimulation canaffect both the atrial-ventricle and the ventricle-ventricle conductiontime intervals and reduce the overall heart rate, resulting in improvedcardiac performance.

In some embodiments, a CRT device receives a communication signal from avagal stimulator and changes its own settings responsively thereto. Forinstance, the CRT device may provide a longer AV time when vagalstimulation is applied, while providing a shorter AV time when nostimulation is applied. Alternatively or additionally, the CRT devicemay apply pacing generally only when vagal stimulation is applied, thusreducing pacing that forces conduction that is not through naturalpathways. Further alternatively or additionally, the CRT device may setthe VV or AV timings as a function of the patient's heart rate,parameters of the vagal stimulator device, or sensor signals from aphysiological sensor.

In some embodiments, both the vagal stimulator and the CRT device areassembled in one integrated unit.

In some embodiments, a vagal stimulator changes its stimulationparameters (e.g., timing within cardiac cycle, amplitude, pulse width,or PPT) to achieve desired AV conduction times and/or QRS duration. Thisvagal stimulator typically comprises a sensor and/or circuitry formeasuring and/or evaluating these stimulation parameters. For differentpatients, or in one patient at different times, the desired conductiontimes may be the optimal conduction times, thus reducing the use of CRT,or the desired conduction times may be longer than optimal times,allowing the CRT to work efficiently.

In some embodiments of the present invention, vagal stimulation asdescribed herein is applied in combination with multi-chamber pacing(e.g., biventricular pacing, biatrial pacing, or pacing of at least oneof the ventricles combined with pacing of at least one of the atria).

Although embodiments of the present invention are described herein, insome cases, with respect to treating specific heart conditions, it is tobe understood that the scope of the present invention generally includesutilizing the techniques described herein to controllably stimulate thevagus nerve to facilitate treatments of, for example, heart failure,atrial fibrillation, and ischemic heart diseases. In particular, thetechniques described herein may be performed in combination with othertechniques, which are well known in the art or which are described inthe references cited herein, that stimulate the vagus nerve in order toachieve a desired therapeutic end.

For some applications, techniques described herein are used to applycontrolled stimulation to one or more of the following: the lacrimalnerve, the salivary nerve, the vagus nerve, the pelvic splanchnic nerve,or one or more sympathetic or parasympathetic autonomic nerves. Suchcontrolled stimulation may be applied to such nerves directly, orindirectly, such as by stimulating an adjacent blood vessel or space.Such controlled stimulation may be used, for example, to regulate ortreat a condition of the lung, heart, stomach, pancreas, smallintestine, liver, spleen, kidney, bladder, rectum, large intestine,reproductive organs, or adrenal gland.

As appropriate, techniques described herein are practiced in conjunctionwith methods and apparatus described in one or more of the followingpatent applications, all of which are assigned to the assignee of thepresent application and are incorporated herein by reference:

-   -   U.S. patent application Ser. No. 10/205,474, filed Jul. 24,        2002, entitled, “Electrode assembly for nerve control,” which        published as U.S. Patent Publication 2003/0050677    -   U.S. Provisional Patent Application 60/383,157 to Ayal et al.,        filed May 23, 2002, entitled, “Inverse recruitment for autonomic        nerve systems”    -   U.S. patent application Ser. No. 10/205,475, filed Jul. 24,        2002, entitled, “Selective nerve fiber stimulation for treating        heart conditions,” which published as U.S. Patent Publication        2003/0045909    -   PCT Patent Application PCT/IL02/00068, filed Jan. 23, 2002,        entitled, “Treatment of disorders by unidirectional nerve        stimulation,” and U.S. patent application Ser. No. 10/488,334,        filed Feb. 27, 2004, in the US National Phase thereof    -   U.S. patent application Ser. No. 09/944,913, filed Aug. 31,        2001, entitled, “Treatment of disorders by unidirectional nerve        stimulation”    -   U.S. patent application Ser. No. 10/461,696, filed Jun. 13,        2003, entitled, “Vagal stimulation for anti-embolic therapy”    -   PCT Patent Application PCT/IL03/00430, filed May 23, 2003,        entitled, “Electrode assembly for nerve control,” which        published as PCT Publication WO 03/099373    -   PCT Patent Application PCT/IL03/00431, filed May 23, 2003,        entitled, “Selective nerve fiber stimulation for treating heart        conditions,” which published as PCT Publication WO 03/099377    -   U.S. patent application Ser. No. 10/719,659, filed Nov. 20,        2003, entitled, “Selective nerve fiber stimulation for treating        heart conditions”    -   A PCT patent application filed May 23, 2004, entitled,        “Selective nerve fiber stimulation for treating heart        conditions”    -   A PCT patent application filed Jun. 10, 2004, entitled, “Vagal        stimulation for anti-embolic therapy”    -   A U.S. patent application Ser. No. ______ filed Jun. 10, 2004,        entitled, “Applications of vagal stimulation”    -   A PCT patent application filed Jun. 10, 2004, entitled,        “Applications of vagal stimulation”    -   A U.S. patent application Ser. No. ______ filed Dec. 22, 2004,        entitled, “Construction of electrode assembly for nerve control”

“Average,” as used herein, including in the claims, is to be understoodbroadly as including any representative value or central tendency of aset of numbers, including arithmetic and geometric mean, median, mode,midrange, and other similar mathematical techniques known in the art.

It will be appreciated by persons skilled in the art that currentapplication techniques described herein may be appropriate forapplication to additional nerves or tissues, such as, for example,cardiac tissue. In addition, techniques described herein may beappropriate for implementation in pacemakers and/or ICDs, mutatismutandis. For example, techniques described herein for configuringand/or regulating the application of an electrical current may beperformed, mutatis mutandis, for applying pacing pulses oranti-arrhythmic energy to the heart.

It will also be appreciated by persons skilled in the art that thepresent invention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. Apparatus comprising: an implantable sensor, adapted to sense anelectrical parameter of a heart of a subject; a first control unit,adapted to apply pulses to the heart responsively to the sensedparameter, the pulses selected from the list consisting of: pacingpulses and anti-arrhythmic energy; an electrode device, adapted to becoupled to a site of the subject selected from the list consisting of: avagus nerve of the subject, an epicardial fat pad of the subject, apulmonary vein of the subject, a carotid artery of the subject, acarotid sinus of the subject, a coronary sinus of the subject, a venacava vein of the subject, a right ventricle of the subject, and ajugular vein of the subject; and a second control unit, adapted to drivethe electrode device to apply to the site a current that increasesparasympathetic tone of the subject and affects a heart rate of thesubject, wherein the first and second control units are not under commoncontrol, and wherein at least one of the control units is adapted tocoordinate an aspect of its operation with an aspect of operation of theother control unit.
 2. The apparatus according to claim 1, wherein thesecond control unit is adapted to generate a communication signalindicative of driving the electrode device to apply the current, andwherein the first control unit is adapted to receive the communicationsignal, and to regulate an aspect of its own operation responsively toreceiving the communication signal.
 3. (canceled)
 4. The apparatusaccording to claim 1, wherein the implantable sensor, the first controlunit, the electrode device, and the second control unit are packaged ina single integrated unit.
 5. The apparatus according to claim 1, whereinthe second control unit is adapted to drive the electrode deviceresponsively to the sensed parameter.
 6. The apparatus according toclaim 1, wherein the aspect of the operation of the first control unitincludes an aspect of timing of the operation of the first control unit,wherein the aspect of the operation of the second control unit includesan aspect of timing of the operation of the second control unit, andwherein the at least one of the control units is adapted to coordinatethe aspect of the timing of the operation of the first control unit withthe aspect of the timing of the operation of the second control unit. 7.The apparatus according to claim 1, wherein the implantable sensor andthe first control unit together comprise an implantable cardioverterdefibrillator (ICD).
 8. The apparatus according to claim 1, wherein theimplantable sensor and the first control unit together comprise apacemaker.
 9. The apparatus according to claim 1, wherein theimplantable sensor and the first control unit together comprise a pulsegenerator.
 10. The apparatus according to claim 1, wherein the secondcontrol unit is configured to reduce a likelihood that the currentcauses the first control unit to falsely detect arrhythmia of thesubject.
 11. The apparatus according to claim 1, wherein the at leastone of the control units is configured to reduce a likelihood of anoccurrence of a “tug-of-war” between the first and second control units.12. The apparatus according to claim 1, wherein the first control unitis programmed with a flag indicative of the presence of the secondcontrol unit, and wherein the first control unit is adapted to withholdcoordinating the aspect of the operation responsively to a value of theflag that indicates that the second control unit is not present.
 13. Theapparatus according to claim 1, wherein the second control unit isprogrammed with a flag indicative of the presence of the first controlunit, and wherein the at least one of the control units is adapted towithhold coordinating the aspect of the operation responsively to avalue of the flag that indicates that the first control unit is notpresent.
 14. The apparatus according to claim 1, wherein the secondcontrol unit is adapted to generate a communication signal when drivingthe electrode device to apply the current, and wherein the first controlunit is adapted to receive the signal, and, responsively thereto, towithhold applying the pulses.
 15. The apparatus according to claim 1,wherein the first control unit is adapted to withhold attempting todetect a next heart beat during an extended blanking period followingdetection of a previous heart beat.
 16. (canceled)
 17. The apparatusaccording to claim 15, wherein the second control unit is adapted todrive the electrode device to apply the current only during the extendedblanking period.
 18. The apparatus according to claim 1, wherein thesite includes the vagus nerve, and wherein the electrode device isadapted to be coupled to the vagus nerve.
 19. The apparatus according toclaim 18, wherein the second control unit is adapted to configure thecurrent to include a stimulating current, which is capable of inducingaction potentials in a first set and a second set of nerve fibers of thevagus nerve, and an inhibiting current, which is capable of inhibitingthe induced action potentials traveling in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set.
 20. The apparatusaccording to claim 18, wherein the second control unit is adapted toconfigure the current to include a stimulating current, which is capableof inducing action potentials in the vagus nerve, and an inhibitingcurrent, which is capable of inhibiting action potentials induced by thestimulating current and traveling in the vagus nerve in an afferentdirection toward a brain of the subject.
 21. The apparatus according toclaim 1, wherein the first control unit is adapted to generate acommunication signal at each detection of a feature of a cardiac cycleof the subject, and wherein the second control unit is adapted toreceive the signal, and to time an aspect of the application of thecurrent responsively to the signal.
 22. (canceled)
 23. The apparatusaccording to claim 1, wherein the second control unit is adapted to,upon detection of suspected arrhythmia, drive the electrode device toapply the current, and to configure the current to reduce a ventricularrate.
 24. The apparatus according to claim 23, wherein the implantablesensor and the first control unit together comprise an implantablecardioverter defibrillator (ICD), and wherein the ICD is adapted toapply defibrillation to the heart if the applied current does notsufficiently reduce the ventricular rate.
 25. The apparatus according toclaim 1, wherein the first control unit is adapted to detect ventricularfibrillation (VF), to generate a communication signal responsive to thedetection, and to withhold generating the signal after the detectionceases, and wherein the second control unit is adapted to receive thesignal, and, responsively thereto, to withhold driving the electrodedevice to apply the current until cessation of the signal.
 26. Theapparatus according to claim 1, wherein the second control unit isadapted to detect ventricular fibrillation (VF), and, responsivelythereto, to withhold driving the electrode device to apply the currentuntil cessation of the VF.
 27. The apparatus according to claim 1,wherein the first control unit is adapted to detect ventriculartachycardia (VT), to generate a communication signal responsive to thedetection, and to withhold generating the signal after the detectionceases, and wherein the second control unit is adapted to receive thesignal, and, responsively thereto, to withhold driving the electrodedevice to apply the current until cessation of the signal.
 28. Theapparatus according to claim 1, wherein the second control unit isadapted to detect ventricular tachycardia (VT), and, responsivelythereto, to withhold driving the electrode device to apply the currentuntil cessation of the VT.
 29. The apparatus according to claim 1,wherein the first control unit is adapted to generate a communicationsignal when applying pulses to the heart, and to withhold generating thesignal when not applying the pulses, and wherein the second control unitis adapted to receive the signal, and, responsively thereto, to withholddriving the electrode device to apply the current until a certain amountof time after cessation of the signal.
 30. The apparatus according toclaim 1, wherein the second control unit is adapted to drive theelectrode device to apply the current during at least one periodselected from the list consisting of: a refractory period of the heart,and a blanking period of the first control unit.
 31. (canceled)
 32. Theapparatus according to claim 1, wherein the first control unit isadapted to apply the pulses only when the heart rate is within a firstset of values, and wherein the second control unit is adapted to drivethe electrode device to apply the current only when the heart rate iswithin a second set of values.
 33. The apparatus according to claim 32,wherein the first and second sets of values are non-overlapping.
 34. Theapparatus according to claim 33, wherein the first set of valuesincludes values greater than 190 beats per minute and less than 60 beatsper minute, and the second set of values includes values between 70 and180 beats per minute. 35-43. (canceled)
 44. Apparatus comprising: anelectrode device, adapted to be coupled to a site of a subject selectedfrom the list consisting of: a vagus nerve of the subject, an epicardialfat pad of the subject, a pulmonary vein of the subject, a carotidartery of the subject, a carotid sinus of the subject, a coronary sinusof the subject, a vena cava vein of the subject, a right ventricle ofthe subject, and a jugular vein of the subject; a sensing element,adapted to sense a physiological parameter of a heart of the subject; animplantable device adapted to apply pulses to the heart, the pulsesselected from the list consisting of: pacing pulses and anti-arrhythmicenergy; and a control unit, adapted to: detect a life-threateningarrhythmia (LTA) responsively to the sensed physiological parameter,responsively to the detection of the LTA, drive the electrode device toapply to the site a current that increases parasympathetic tone of thesubject, determine whether the LTA has been resolved, responsively to adetermination that the LTA has not been resolved, determine whether todrive the implantable device to apply the pulses to the heart,responsively to an affirmative determination to drive the implantabledevice, drive the implantable device to apply the pulses to the heart,and responsively to a determination not to drive the implantable device,drive the electrode device to apply the current to the site.
 45. Theapparatus according to claim 44, wherein the control unit is adapted tochange a parameter of the current applied to the site, after thedetermination not to drive the implantable device.
 46. The apparatusaccording to claim 44, wherein the implantable device comprises animplantable cardioverter defibrillator (ICD).
 47. The apparatusaccording to claim 44, wherein the implantable device comprises apacemaker.
 48. The apparatus according to claim 44, wherein theparameter includes a feature of an electrocardiogram (ECG) signal, andwherein the sensing element is adapted to sense the feature.
 49. Theapparatus according to claim 44, wherein the control unit is adapted todetermine to drive the implantable device to apply the pulses only ifthe control unit determines that only driving the electrode device toapply the current is unlikely to resolve the LTA.
 50. Apparatuscomprising: an electrode device, adapted to be coupled to a site of asubject selected from the list consisting of: a vagus nerve of thesubject, an epicardial fat pad of the subject, a pulmonary vein of thesubject, a carotid artery of the subject, a carotid sinus of thesubject, a coronary sinus of the subject, a vena cava vein of thesubject, a right ventricle of the subject, and a jugular vein of thesubject; a sensing element, adapted to sense a physiological parameterof a heart of the subject; an implantable device adapted to apply pulsesto the heart, the pulses selected from the list consisting of: pacingpulses and anti-arrhythmic energy; and a control unit, adapted to: drivethe electrode device to apply to the site a current that increasesparasympathetic tone of the subject, detect a life-threateningarrhythmia (LTA) responsively to the sensed physiological parameter,responsively to the detection of the LTA, modify at least one currentparameter of the applied current, determine whether the LTA has beenresolved, responsively to a determination that the LTA has not beenresolved, determine whether to drive the implantable device to apply thepulses to the heart, responsively to an affirmative determination todrive the implantable device, drive the implantable device to apply thepulses to the heart, and responsively to a determination not to drivethe implantable device, modify one or more current parameters of theapplied current.
 51. The apparatus according to claim 50, wherein theimplantable device comprises an implantable cardioverter defibrillator(ICD).
 52. The apparatus according to claim 50, wherein the implantabledevice comprises a pacemaker.
 53. The apparatus according to claim 50,wherein the parameter includes a feature of an electrocardiogram (ECG)signal, and wherein the sensing element is adapted to sense the feature.54. The apparatus according to claim 50, wherein the control unit isadapted to determine to drive the implantable device to apply the pulsesonly if the control unit determines that only driving the electrodedevice to apply the current is unlikely to resolve the LTA.
 55. A methodcomprising: sensing, from within a body of a subject, an electricalparameter of a heart of the subject; applying, from a first implantationsite within the body, pulses to the heart responsive to the parameter,the pulses selected from the list consisting of: pacing pulses andanti-arrhythmic energy; applying, at a second implantation site withinthe body, a current that increases parasympathetic tone of the subjectand affects a heart rate of the subject, the second implantation siteselected from the list consisting of: a vagus nerve of the subject, anepicardial fat pad of the subject, a pulmonary vein of the subject, acarotid artery of the subject, a carotid sinus of the subject, acoronary sinus of the subject, a vena cava vein of the subject, a rightventricle of the subject, and a jugular vein of the subject; andcoordinating an aspect of applying the pulses with an aspect of applyingthe current, without providing a controller that regulates both theapplying of the pulses and the applying of the current.
 56. The methodaccording to claim 55, wherein applying the current at the secondimplantation site comprises applying the current responsively to thesensed electrical parameter.
 57. The method according to claim 55,wherein applying the current comprises generating a communication signalindicative of applying the current, and wherein applying the pulsescomprises receiving the communication signal, and regulating an aspectof the applying of the pulses responsively to receiving thecommunication signal.
 58. The method according to claim 55, whereinsensing the electrical parameter comprises implanting, in the subject, adevice for sensing the electrical parameter, and wherein applying thepulses comprises applying the pulses from the device.
 59. (canceled) 60.The method according to claim 58, wherein the aspect of applying thepulses includes an aspect of timing of applying the pulses, wherein theaspect of applying the current includes an aspect of timing of applyingthe current, and wherein coordinating comprises coordinating the aspectof timing of applying the pulses with the aspect of timing of applyingthe current.
 61. The method according to claim 58, wherein sensing theparameter comprises analyzing the parameter to detect arrhythmia of thesubject, and wherein coordinating comprises coordinating so as to reducea likelihood that applying the current causes false detection of thearrhythmia.
 62. The method according to claim 58, wherein sensing theparameter comprises identifying a stimulus artifact of the currentapplication as being a stimulus artifact of the current application. 63.The method according to claim 58, wherein applying the current comprisesgenerating a communication signal when applying the current, and whereinapplying the pulses comprises receiving the signal, and, responsivelythereto, withholding applying the pulses.
 64. The method according toclaim 58, wherein sensing the parameter comprises withholding attemptingto detect a next heart beat during an extended blanking period followingdetection of a previous heart beat.
 65. The method according to claim58, wherein the second implantation site includes the vagus nerve, andwherein applying the current comprises applying the current to the vagusnerve.
 66. The method according to claim 58, wherein applying thecurrent comprises applying the current during at least one periodselected from the list consisting of: a refractory period of the heart,and a blanking period of the device.
 67. The method according to claim58, wherein applying the pulses comprises applying the pulses only whenthe heart rate is within a first set of values, and applying the currentcomprises applying the current only when the heart rate is within asecond set of values.
 68. The method according to claim 67, wherein thefirst and second sets of values are non-overlapping. 69-74. (canceled)75. A method for surgically implanting an electrode device in a vicinityof a nerve, comprising: placing the electrode device around the nerve;introducing conductive solution into the electrode device such that thesolution is in contact with both the electrode device and the nerve;during implantation of the electrode device, measuring an impedancebetween one or more electrodes of the electrode device and an electricalcontact point in electrical communication with the electrode device; andresponsively to the impedance measurement, determining whether theelectrodes are positioned appropriately, and whether sufficientconductive solution is in the electrode device.
 76. The method accordingto claim 75, wherein the conductive solution includes saline solution,and wherein introducing the conductive solution comprises introducingthe saline solution.
 77. The method according to claim 75, wherein thenerve includes a vagus nerve, and wherein placing the electrode devicearound the nerve comprises placing the electrode device around the vagusnerve.
 78. The method according to claim 75, comprising, responsively tothe impedance measurement, determining whether the electrodes arecorrectly sized for the nerve.
 79. The method according to claim 75,wherein determining whether the electrodes are positioned appropriatelycomprises determining whether the electrodes are in good electricalcontact with the nerve.
 80. The method according to claim 75, whereindetermining whether the electrodes are positioned appropriatelycomprises interpreting a value of the impedance measurement between 100and 300 ohms as an indication that the electrodes are not positionedappropriately.
 81. The method according to claim 75, wherein determiningwhether the electrodes are positioned appropriately comprisesinterpreting a value of the impedance measurement between 300 and 1000ohms as an indication that the electrodes are positioned appropriately.82. The method according to claim 75, wherein determining whethersufficient conductive solution is in the electrode device comprisesinterpreting a value of the impedance measurement greater than 1000 ohmsas an indication that insufficient conductive solution is in theelectrode device.
 83. The method according to claim 75, wherein the oneor more electrodes of the electrode device include at least first andsecond electrodes, wherein the electrical contact point includes thefirst one of the electrodes, and wherein measuring the impedancecomprises measuring the impedance between the first and secondelectrodes.
 84. The method according to claim 75, wherein the electricalcontact point is located outside of the electrode device, and whereinmeasuring the impedance comprises measuring the impedance between theone or more electrodes and the electrical contact point located outsideof the electrode device.
 85. A method comprising: sensing, from within abody of a subject, a physiological parameter of a heart of the subject;detecting a life-threatening arrhythmia (LTA) responsively to the sensedphysiological parameter; responsively to the detection of the LTA,applying to a site of the subject a current that increasesparasympathetic tone of the subject, the site selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a coronary sinus of thesubject, a vena cava vein of the subject, a right ventricle of thesubject, and a jugular vein of the subject; determining whether the LTAhas been resolved; responsively to a determination that the LTA has notbeen resolved, determining whether to apply, from within the body,pulses to the heart selected from the list consisting of: pacing pulsesand anti-arrhythmic energy; responsively to an affirmative determinationto apply the pulses, applying the pulses to the heart; and responsivelyto a determination not to apply the pulses, applying the current to thesite.
 86. The method according to claim 85, comprising changing aparameter of the current applied to the site, after the determinationnot to apply the pulses.
 87. The method according to claim 85, whereinthe pulses include anti-arrhythmic energy.
 88. The method according toclaim 85, wherein the pulses include pacing pulses.
 89. The methodaccording to claim 85, wherein the parameter includes a feature of anelectrocardiogram (ECG) signal, and wherein sensing comprises sensingthe feature.
 90. The method according to claim 85, wherein determiningcomprises determining to apply the pulses only if applying the currentis determined to be unlikely to resolve the LTA.
 91. A methodcomprising: applying to a site of a subject a current that increasesparasympathetic tone of the subject, the site selected from the listconsisting of: a vagus nerve of the subject, an epicardial fat pad ofthe subject, a pulmonary vein of the subject, a carotid artery of thesubject, a carotid sinus of the subject, a coronary sinus of thesubject, a vena cava vein of the subject, a right ventricle of thesubject, and a jugular vein of the subject; sensing, from within a bodyof the subject, a physiological parameter of a heart of the subject;detecting a life-threatening arrhythmia (LTA) responsively to the sensedphysiological parameter; responsively to the detection of the LTA,modifying at least one current parameter of the applied current;determining whether the LTA has been resolved; responsively to adetermination that the LTA has not been resolved, determining whether toapply, from within the body, pulses to the heart selected from the listconsisting of: pacing pulses and anti-arrhythmic energy; responsively toan affirmative determination to apply the pulses, applying the pulses tothe heart; and responsively to a determination not to apply the pulses,modifying one or more current parameters of the applied current.
 92. Themethod according to claim 91, wherein the pulses include anti-arrhythmicenergy.
 93. The method according to claim 91, wherein the pulses includepacing pulses.
 94. The method according to claim 91, wherein theparameter includes a feature of an electrocardiogram (ECG) signal, andwherein sensing comprises sensing the feature.
 95. The method accordingto claim 91, wherein determining comprises determining to apply thepulses only if applying the current is determined to be unlikely toresolve the LTA.